CN100386083C - Methods of using vitamin d compounds in the treatment of myelodysplastic syndromes - Google Patents

Methods of using vitamin d compounds in the treatment of myelodysplastic syndromes Download PDF

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CN100386083C
CN100386083C CNB2003801073796A CN200380107379A CN100386083C CN 100386083 C CN100386083 C CN 100386083C CN B2003801073796 A CNB2003801073796 A CN B2003801073796A CN 200380107379 A CN200380107379 A CN 200380107379A CN 100386083 C CN100386083 C CN 100386083C
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M·J·怀特豪斯
J·G·柯德
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Abstract

Methods of treating MDS, or ameliorating a symptom thereof, are disclosed. Specific methods encompass the administration of one or more vitamin D compounds, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with one or more additional active agents. Other methods include intermittent administration of a high dose of one or more vitamin D compounds, or a pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, alone or in combination with one or more additional active agents. Such intermittent administration allows high doses of the vitamin D compounds to be administered while minimizing or eliminating hypercalcemia.

Description

The method for preparing treatment osteomyelodysplasia syndrome medicament with vitamin d compounds
Invention field
The present invention partly relates to treatment osteomyelodysplasia syndrome (MDS) or alleviates the method for its one or more symptoms, this method comprises and gives vitamin d compounds, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, separately the treatment or with other medicine combined therapy.Can give the vitamin d compounds treatment MDS of high dose or alleviate its symptom, adopt the discontinuity administration can avoid side effect such as hypercalcemia.
Background of invention
The pathology of MDS
Osteomyelodysplasia syndrome (MDS) refers to panoramic hematopoietic stem cell disease.The feature of MDS is form and ripe impaired (medullary cell generates unusual) of bone marrow medullary epithelium, because the peripheral blood cells that invalid hemopoietic causes minimizing and develop into the various danger of acute leukemia.See The Merck Manual953 (the 17th edition, 1999) and List et al, 1990, J.Clin.Oncol.8:1424-1441.
MDS mainly is old people's a disease, and the age of onset median was 70 years old age.These patient's age medians are 65 years old, and the age of onset scope is early to more than 20 year old, and evening was to 80 years old or older.Yet the osteomyelodysplasia syndrome also may influence the child, and they have the clinical manifestation similar to the adult.See Heany et al, 1999, New Eng.J.Med.340:1649-60.There is genetic abnormality among the MDS sick child about 30%,, thinks that these children are to osteomyelodysplasia syndrome susceptible as Down's syndrome.
The feature of MDS has constitutional or Secondary cases, adopts some chemotheraping preparation or radiotherapy malignant tumor and the patient of surviving has the high incidence that develops into Secondary cases MDS or acute leukemia.See Zeidman etal, 1995, Haematologia (Budap) 27:23-8.Approximately the patient of 60-70% does not have obvious contact history or the reason of MDS, and they are categorized as constitutional MDS patient.Yet some patient 10-15 before this disease of outbreak may exist non-specific contact harmful chemical or ray history.The contact chemical compound includes but not limited to that benzene, Insecticides (tech) ﹠ Herbicides (tech) and antifungal increase relevant with the MDS sickness rate.See West et al, 2000, Blood.95:2093-7 and Goldberg et al, 1990, Cancer Res.50:6876-81.The MDS or the acute leukemia that take place behind contact genotoxicity chemotherapeutics or the ray when Secondary cases MDS refers to treat irrelevant malignant tumor.See Zeidman et al, 1995, Haematologia (Budap) 27:23-8.High rate that these medicines are unusual with contacting the after stain colour solid and trouble MDS or acute leukemia diagnosis are relevant.
In addition, MDS and serious cytopenia and the clinical complication followed thereof are relevant.May showing of these cytopenias comprises: because of neutrophilic leukocyte minimizing risk of infection increase and neutrocyte function bad, take place hemorrhagely because of thrombocytopenia and platelet function are bad, reach anemia and the fatigue that causes.Other complication is that myelofibrosis takes place, and it can quicken, and cytometry descends and raising blood transfusion demand.See Heany etal, 1999, New Eng J.Med.340:1649-60 and Lambertenghi-Deliliers et al, 1992, Leuk.Lymphoma.8:51-5.The main clinical problem of other of patient MDS is that this disease may develop into acute myeloid leukaemia (AML).These any or all performances can cause shortening patient's time-to-live.
When MDS, may cause having of initial hematopoietic stem cell injuries in the other factors: cytotoxicity chemotherapy, ray, virus, chemistry contact and genetic predisposition.The early stage principal character of MDS is cytopenia, comprises anemia, neutrophilic leukocyte minimizing and thrombocytopenia.Each patient's difference of this sick course of disease, some case shows as chronic disease, and other shows as progressivity, and clinical disease course is extremely short, is transformed into acute leukemia rapidly.
The international group of hematologist, France-U.S.-Britain (FAB) cooperative groups is divided into 5 kinds of subgroups with the MDS disease, and they are distinguished mutually with acute myeloid leukaemia.See The Merck Manual 954 (the 17th edition, 1999); Bennett et al, 1985, Ann.Intern.Med.103:620-625; And Besa, 1992, Med.Clin.North Am.76 (3): 599-617.Classification method according to FAB; the refractory anemia that two subgroups are arranged; feature be bone marrow have 5% or less than pith mother cells: (1) refractory anemia (RA) and (2) have the RA (RARS) of annular sideroblast; it is defined as on the form 15% erythroid cells for having unusual annular sideroblast, has reflected the abnormal accumulation of ferrum in the mitochondrion.Besa，1992，Med.Clin.North Am.76(3)：599-617。Two kinds of pith mother cellss are also arranged greater than 5% refractory anemia subgroup: (1) with the RA (RAEB) of excessive blast cell, is defined as the pith mother cells of 6-20% and (2) RAEB (RAEB-T) in transforming, and the pith mother cells of 21-30% is arranged.At last, the 5th kind of MDS of difficult classification is called MLC (CMML).This subclass can have the pith mother cells of any percentage ratio, but exists monocytosis to reach 1000/dL or higher.On seeing; Harris et al, 1999, J.Clin.Oncol.17:3835-49.
Recently, World Health Organization (WHO) has proposed the MDS categorizing system, is called international prognosis marking system (IPSS).This system is divided into 4 kinds of prognosis types according to haematogonium percentage ratio, cytogenetics subgroup and cytopenia quantity with the MDS disease.See Greenberg et al, 1998, Blood.89:2079-88 and Bennett, 2000, Int.J.Hematol.72:131-33.Though the FAB categorizing system is still useful, IPSS has predicted that better disease is to the progress of acute myeloid leukaemia (AML) and patient's survival period.According to IPSS, the setting value of each class variable shown in the following table 1 is added together, determine the prognosis classification of the MDS shown in the following table 2.See Greenberg etal, 1998, Blood.89:2079-88.The median of low danger patient's MDS time-to-live is 5.7 years, and the median of high-risk patient's MDS time-to-live is 0.4 year.Meta-1 and-median of patient's 2MDS time-to-live was respectively 3.5 years and 1.2 years.On seeing.
Table 1
Figure C20038010737900071
Table 2
The class of risk Comprehensive grading
Low 0
Meta-1 0.5-1.0
Meta-2 1.5-2.0
High ≥2.5
The MDS of the U.S. is definite, and sickness rate is not known.Thought that MDS was the provincialism disease in previous 1976, incidence rate estimates that 1500 new patients are arranged every year.Have only pith mother cells just to think this disease at that time less than the patient of `5%.(1999) statistics estimates that 13,000 new cases are arranged every year recently, and annual about 1000 examples of child surpass chronic lymphocytic leukemia, become the modal type of leukemia in the Western Hemisphere.The morbidity percentage rate increases may be because to the understanding of this disease and the improvement of diagnostic criteria.This disease sees the whole world.
The treatment of MDS at present
The treatment of MDS at present is mainly according to the concrete phase mechanism of this disease process.For young patient, the bone marrow of transplanting the coupling donor is preferred Therapeutic Method, but the gerontal patient is not the candidate of this damaging intervention usually, because many people have Anemia and depend on blood transfusion.Can adopt hemopoietic growth factor to stimulate hemocyte to grow, this patient to a subgroup is effective.Other treatment comprises supportive infusion erythrocyte and platelet associating aggressive treatment infection.In addition, also assessed the effect of the potential medicine treatment osteomyelodysplasia syndrome of many other types, but success is very limited.This class treatment comprises the derivant of immunomodulator, cellulotoxic preparation, the preparation that can influence rna transcription, vitamin A, E and K, and the energy specificity is in conjunction with preparation, signal conduction depressant drug, cytoprotective preparation and the arsenical of MDS associated biomolecule target.
Bone marrow transplantation applied to poor prognosis or late period MDS patient.See Epstein et al, 1985, Surg.Ann.17:23-29.Unfortunately, bone marrow transplantation all is damaging and painful to receptor and donor, can cause the receptor serious in addition the lethal complication.The allograft treatment of standard depends on maximum chemotherapy tolerance dose and total irradiation comes radical curing of disease and immunosuppressant receptor that graft is survived and prevent graft to be ostracised.Transplanting the back adopts immunosuppressant (medicine) to induce tolerance and control graft versus host disease.Therefore, allograft must be limited to the patient who treats young healthy, and must execute in special inpatient unit and control.Under best-case, transplant relevant mortality rate and be approximately 20-25%, may be up to 30-35%.See Deeg et al, 2000, Leuk.Res.24:653-63.Reason for this reason, the old people more than 55 years old transplants seldom, and is limited to fatal disease.Symptomatic obstinate anemia patient transfuses blood and the dangerous associated that overloads of propagation, transfusion reaction and the cardiovascular of infectious disease clinically repeatedly.In addition, repeatedly blood transfusion may cause the Secondary cases hemochromatosis as 20-30 blood transfusion, and this is a kind of disease that needs to pay close attention to serum levels of iron at least, often needs to carry out every day (ion) chelating therapy.
Hemopoietic growth factor or cytokine are treatment MDS and the another kind of method that stimulates the hemocyte growth.See Dexter, 1987, Cell Sci.88:1-6; Moore, 1991, Annu.Rev.Immunol.9:159-91 and Besa, 1992, Med.Clin.North Am.76 (3): 599-617.Hemopoietic growth factor is the hormone that participates in the hemocyte forming process.Its treatment relates to stimulates the stem cells hyperplasia that can ownly upgrade generation pedigree specificity progenitor in a small amount, breeds then and differentiation becomes sophisticated circulation hemocyte.See Metcalf, 1985, Science.229:16; Dexter, 1987, Cell Sci.88:1-6; Golde et al, 1988, Scientific American:62-71; Tabbara etal, 1991, Anti-Cancer Res.11:81-90; Ogawa, 1989, Environ.Health Persp.80:199-207; And Dexter, 1989, Macl.Bull.45:337-49.The somatomedin of understanding most characteristic comprises: erythropoietin (EPO), granulocyte-macrophage colony stimutaing factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF).Remove and to induce the propagation that can cause the coup injury blood progenitor cell and to divide outside the pale of civilizationly, this type cytokines also can activate some functions of mature blood cell, comprises the migration that influences ripe hematopoietic cell.See Stanley etal, 1976, J.Exp.Med.143:631-47; Schrader et al, Proc Natl.Acad.Sci.USA., 1981,78:323-7; Moore et al, 1980, J.Immunol.125:1302-5; Kurland et al, Proc.Natl.Acad.Sci.USA., 1979,76:2326-30; Handman et al, 1979, J.Immunol.122:1134-7; Vadas et al, 1983, Blood.61:1232; Vadas et al, 1983, J.Immunol.130:795-9; With Weisbart et al, 1986, J.Immunol.137:3584-87.
Hemopoietic growth factor such as the r-HuEPO (erythropoietin of reorganization that reorganization produces; Erythropoietin-α;
Figure C20038010737900091
Amgen;
Figure C20038010737900092
Ortho Biotech) and the r-metHuG-CSF (Filgrastim of reorganization; The Filgrastim;
Figure C20038010737900093
Amgen) in a subgroup patient, can support the generation of erythrocyte (RBC) and neutrophilic leukocyte effectively respectively.See Hellstroem-Lindberg et al, 1998, Blood.92:68-75 and Hellstroem-Lindberg et al, 1997, Br.J.Haematol.99:344-51.In several big communities is that the hemoglobin level of following raises and causes the improvement of quality of life in cancer patient's test on basis.See for example Glaspy et al, 1997, J.Clin.Oncol.15:1218-34 and Detetri et al, 1998, J.Clin.Oncol.16:3412-25.
Yet the anemia of MDS usually is serious and hemopoietic growth factor or cytokine refractory.Anemia may worsen the common disease of gerontal patient, includes but not limited to: congestive heart failure, coronary artery disease and chronic lung disease.Single have only about 20% patient to respond with EPO, and EPO, G-CSF about 40% patient of administration together respond.See Hellstroem-Lindberg et al, 1998, Blood.92:68-75 and Hellstroem-Lindberg et al, 1997, Br.J.Haematol.99:344-51.Serum erythropoietin level often can be estimated EPO is responded less than 200mU/ml, but the reactive stage that depends on disease, the response rate that refractory anemia and band form siderocyte's refractory anemia is 21%, but excessive blast cell refractory anemia response rate has only 8%.See Hellstroem-Lindberg et al, 1997, Br.J.Haematol.99:344-51 and Hellstroem-Lindberg., 1995, Br.J.Haematol.89:67-71.Therefore, can not effectively treat all patients with EPO, G-CSF or other growth factor for treating, or even most of MDS patient.
Other somatomedin of drug treatment MDS comprises: thrombopoietin, interferon-' alpha ', il-1, interleukin-2, interleukin-3, interleukin-6, interleukin-8, interleukin-11 and il-1 2.Though many these factors have shown good prospect in external and preclinical study, clinical examination so far seldom or unsuccessful.See Schipperus et al, 1991, Br.J.Haematol.77:515-22; Ganser et al, 2000, Ann.Hematol.79:30-5; Musto et al, 2001, Haematologica.86:44-51; Gordon, Semin.Hematol.1999,36 (4Suppl 6): 21-4; Zwierzina et al, 1993, Scand J.Immunol.37:322-8; Estey et al, 2002, Blood.99:4343-9; Pan et al, 12000, Leukemia.14:1634-41; Hofmann et al, 1999, Eur.J.Haematol.62aaaaaaaaaaaaaaa; 336-40; Hofmann et al, 1999, Ann.Hematol.78:125-30; Haznedaroglu et al, 2002, Clin.Appl.Thromb.Hemost.8:193-212; With Ogata et al, 2000, Int J.Hematol.72:173-7.
Carried out the derivant with immunomodulator, cellulotoxic preparation, the preparation that can influence rna transcription, vitamin A, E and K, the energy specificity is in conjunction with the trial of preparation, signal conduction depressant drug, cytoprotective preparation and the arsenical treatment MDS of MDS associated biomolecule target.For example, may comprise as the immunomodulator of MDS therapeutic agent after tested: antithymocyte globulin (ATG), antilymphocyte globulin (ALG), thalidomide, prednisone, cyclosporin A (CyA), dexamethasone and pentoxifylline.For example see: Molldremet al, 2002, Ann.Intern.Med.137:156; Rong et al, 2002, Eur.J.Haematol.68:210; Tsirigotis et al, 2002, Leuk.Res.26:965; Hisconmex et al, 2001, Leuk.Lympgoma42:665; Ohga et al, 2002, Br.J.Haematol.118:313; Greipp, 2000, Curr.Treat.Options.Oncol.1:119-26; With Raza et al, 2000, Hematol.5:274-84.The cellulotoxic preparation of test comprises: cytosine arabinoside, melphalan, topotecan, fludarabine, etoposide, O-Demethyldaunomycin, daunorubicin, mitoxantrone, cisplatin, paclitaxel and cyclophosphamide.For example see: Garcia-Manero et al, 2002, Haematoiogica.87:804; Beran et al, 2001, Cancer 92:1999; Sackmann-Muriel et al, 1996, Leuk.Res.20:973; Oosterveld et al, 2002, Leukemia 16:1615; Hisconmex etal, 2001, Leuk Lymphoma 42:665; Denzlinger et al, 2000, Br.J.Haematol.108:93; Oosterveld et al, 2002, Leukemia 16:1615; With Lee et al, 2002, Am.J.Hematol.68:237.
In addition, the potential therapeutic agent of MDS that can influence rna transcription after tested comprises: decitabing, 5-azacytidine, depsipeptides and phenyl butyrate.For example see Daskalakis et al, 2002, Blood 100:2957; Gryn etc., 2002, Leuk.Res.26:893; Ballard etc., 2002, Curr.Med.Chem.9:471; Imanishi et al, 2002, J.Clin.Endocrinol.Metab.87:4821; Silvermann et al, 2002, J.Clin.Oncol.20:2429; With Gore et al, 2002, Clin.Cancer.Res.8:963-970.Vitamin A, E and the K derivant that can be used as MDS treatment usefulness through assessment comprise all trans retinoic acids, 13-suitable-tretinoin, tocopherol and Menaquinone K6.For example see Stasi et al, 2002, Blood.99:1578; Hofmann et al, 2000, Leukemia 14:1583; Takami et al, 2002, Ann.Hematol.81:16; With Besa et al, 1998, Leuk.Res.22:741.Potential therapeutic preparation that after tested can specific bond MDS associated biomolecule target comprises: anti-VEGF, gemtuzumab ozogamicin and TNFR:Fc.For example see Verstovsek et al, 2002, Br.J.Haematol.118:151; List, 2002, Oncologist.7Suppl 1:39; With Rosenfeld et al, 2002, Leuk.Res.26:721.Once attempted to comprise: method Buddhist nun's inhibitors such as Zarnestra as the signal transduction inhibitor of MDS treatment preparation TMAnd Sarasar TMWith tyrosine kinase inhibitor such as SU5416, SU6668 and PTK787/ZK222584.For example see Kurzrock, 2002, Semin.Hematol.39 (3Suppl 2): 18; Cortes et al, 2002, Semin.Hematol.39 (3 Suppl 2): 26; List, Oncologist 7 Suppl1:39 (2002); With Cheson et al, 2000, Semin.Oncol.27:560.At last, cytotoxicity preparation and the arsenical that can be used as the potential therapeutic dose of MDS through assessment is respectively A Misiting and arsenic trioxide.For example see Arboscello et al, 2002, AntiCancer Res.22:1819; Invernizzi et al, 2002, Br.J.Hematol.118:246; And Miller, 2002, Oncologist 7 Suppl 1:14.An exception, these treatments neither one in MDS patient can produce notable therapeutic effect indubitablely.
Observing fully in the above-claimed cpd of test as the potential medicine of MDS, a medium exception to poor results is a 5-azacytidine.The Silvermann report, subcutaneous injection 75mg/m every day 25-azacytidine after 28 days the 7th day has 60% patient to have partial reaction at least, and 7% patient has complete reaction.See Silvermann et al, 2002, J.Clin.Oncol.20:2429.Yet this therapeutic scheme has several shortcomings.5-azacytidine is poison extremely, can cause the serious patient De Evil heart vomiting of administration.Also have, the administration of this scheme is to patient's inconvenience, during the treatment patient must every day the clinic execute and control.At last, give 5-azacytidine and can cause earlier that MDS patient's cytopenia increases the weight of, improve then, this is harmful or deadly to some patient.Therefore still need safe and effective procedure to treat and handle MDS.The method that particularly can effectively treat relevant anemia of MDS and minimizing RBC blood transfusion demand will be clinical benefit.
Element-vitamine compound
Vitamin D is that vitamin D receptor is had affinity, participates in the non-trade mark term of a compounds of group of calcium and phosphorus metabolism physiological regulation.See Harrison ' s Principles of Internal Medicine:Part Eleven, volumes such as " bone and mineral metabolism disease " E.Braunwald, 1987, Mcgraw-Hill, New York, the 335th chapter, 1860-1865 page or leaf; Stumpf etc., 1979, Science.206:1188-90 and Holick, 1995, Bone.17:107S-11S.Vitamin D has shown complicated effect and synthesis mechanism.Skin through ultraviolet radiation from 7-dehydrocholesterol synthesis of vitamin d 3.The congener vitamin D2 of vitamin D3 can absorb from diet.The continuous hydroxylation reaction of the secondary of vitamin D2 is that its complete biological activity is necessary.For the first time hydroxylation occurs in the liver, causes forming 25-hydroxyvitamin D3, and hydroxylation occurs in the kidney for the second time, causes forming the Johnson ﹠ Johnson thing metabolite of vitamin D: 1 α, 25-dihydroxy vitamin d3 (being also referred to as calcitriol (Calcitriol)).
Calcitriol is being kept the homoiostasis of calcium by regulating intestinal absorption, the secretion of urine and bone activity.May bring into play these effects by genome and non-genomic group approach.Calcitriol has mediated the genome reaction in conjunction with the receptor in the nucleus (VDR).VDR is a kind of part-activatory transcription factor, can activate transcribing of vitamin D response element institute's regulator gene in the promoter/enhancer zone that is subjected to them.。See Mangelsdorf et al, 1995, Cell.83:835-9.Non-genomic group approach is subjected to a kind of mediation of also not knowing the membrane-bound receptor of characteristic at present.
In addition, found that the VDR among the various organ cells does not participate in the homoiostasis of calcium.See Miller et al, 1992, Cancer Res.52:515-520.Except that son influenced the homoiostasis of calcium, vitamin D compounds also related to the adjusting of osteogenesis, immunne response, the adjusting of pancreatic beta cell excreting insulin, the function of muscle cell and the differentiation and the growth of epithelium and hemopoietic tissue.
Carried out utilizing the trial of vitamin D compounds treatment cancer.For example, vitamin D compounds and congener rely on them to induce the leukocyte differentiation to become the ability of non-pernicious macrophage (mononuclear cell), and have strong anti-leukocythemia liveness, thereby can be used for treating leukemia.See the United States Patent (USP) 4,594,340 of the United States Patent (USP) 4,391,802 of Suda etc. and Partridge etc.The antiproliferative of calcitriol and other vitamin D3 congener and differentiation be it was reported and can be treated carcinoma of prostate.See the United States Patent (USP) 5,795,882 of Bishop etc.Also known vitamin D compounds relates to the treatment skin carcinoma and (sees Chida et al, 1985, Cancer Res.45:5426-5430), colon cancer (is seen Diaman et al, 1987, Cancer Res.47:21-25) and pulmonary carcinoma (see Sato et al, 1982, J ExpMed.138:445-446).The critical treatment purposes of other report vitamin D summary to some extent in the United States Patent (USP) 6,034,079 of Rodriguez etc.
Vitamin D compounds also can with the other medicines preparation, specifically be that cytotoxicity preparation administering drug combinations is treated excess proliferative disease.For example, proved that the cell of anticipating hyper-proliferative with vitamin D compounds uses the cytotoxicity preparation for treating then, can strengthen effect (United States Patent (USP) 6,087,350 and 6,559,139 of this cytotoxicity preparation.
Can cause substantial treatment benefit though give vitamin D compounds, treat cancer with them and be subjected to the active serious restriction of these compounds affect calcium metabolism.When effectively using required level in vivo, vitamin D compounds can pass through their inherent calcium activity that rises, and induces remarkable rising and potential deleterious calcium level.Therefore, be subjected to the obstruction of hypercalcemia danger or seriously restriction with calcitriol and other vitamin D compounds treatment cancer or MDS clinically.
Proved general hypercalcemia problem can by " the high dose pulse gives " (HDPA) active vitamin D compounds of sufficient dosage overcome, simultaneously can avoid taking place serious hypercalcemia thereby observe anti--multiplication effect.According to United States Patent (USP) 6,521,608, give vitamin D compounds and be no more than per three days once, for example weekly, dosage at least 0.12 μ g/kg every day (the people 8.4 μ g of 70kg).United States Patent (USP) 6,521, pharmaceutical compositions for use contains the active vitamin D compounds of 5-100 μ g in 608 the HDPA scheme, can be oral, dosage form in the intravenous, intramuscular, part, transdermal, buccal, intranasal, tumor, or other dosage form gives.In a clinical trial phase, give intractable malignant tumor patient calcitriol once in a week, the HDPA of calcitriol shows that toxicity that has produced no dose limitation and the calcitriol average peak level that produces are in therapeutic domain.Beer et al，Cancer，91：2431-39(2001)。
Give vitamin D compounds treatment MDS
Though MDS can not get clinical preceding animal model, it is reported that calcitriol can change the growth of external myeloid progenitor, and promotes the growth of monokaryon CFU-GM in dosage dependence mode.See Swanson et al, 1986, Blood.67:1154-1161.In addition, prompting on evidence may lack calcitriol in the part in some MDS patient's the bone marrow microenvironment.See Blazsek et al, 1996, Cancer Detect Prevent.20:31-42.It seems that calcitriol can improve the needs that hemodialysis is analysed patient's anemia and reduced the erythropoiesis medicine.See Goicoechea et al, 1998, Nephron.78:23-27.Though the clinical preceding data of relevant employing calcitriol treatment MDS all is positive, calcitriol is limited on scope as the clinical examination result of medicine, and is medium in the reaction.See Morosettiet al, 1996, Semin.Hematol.33:236-245.A reason that produces these results is that the calcitriol that only gives 2 μ g every day has been induced hypercalcemia.See Koeffler et al, 1985, Cancer Treat.Rep.69:1399-1407.The calcitriol that gives the highest 0.75 μ g/ of MDS patient days does not just have hypercalcemia.See Mellibovsky et al, 1998 Brit.J.Haemotol.100:516-520.The vitamin D compounds dosage that these research reports are said them provides certain benefit to the MDS patient of some type, does not cause patient's hypercalcemia but can not improve these dosage to more effective level.
Past and present review for the treatment of to MDS show that existing many potential medicines have also been tested the ability of they treatment MDS.Yet these medicine neither ones obtain clear and definite success in clinical assessment.Really, the medicine that does not still have FDA to ratify meets the treatment index of this disease.See List, 2002, Oncologist7 (Suppl 1): 39-49.In addition, manyly have more nocuous therapy, be not suitable for most of MDS patients as bone marrow transplantation and high dose chemotherapy, because they are older weak.On seeing.Therefore still pressing for safe and effective procedure treats MDS or alleviates its symptom.The method that particularly can effectively treat relevant anemia of MDS and minimizing blood transfusion demand will have clinical benefit.Calcitriol and other vitamin D compounds have shown such clinical benefit, but they are sent out hypercalcemia as the purposes predisposition of curative drug and are restricted.Therefore, need to treat the method that MDS can not cause bad and dangerous side effect such as hypercalcemia simultaneously.
The list of references that this paper quotes or discusses does not constitute admits that they are prior to technology of the present invention.
Summary of the invention
The present invention includes treatment osteomyelodysplasia syndrome (MDS) or alleviate its symptom, the method and composition of MDS anemia particularly, this method comprises the patient's vitamin d compounds that needs, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, can avoid simultaneously or at utmost reduce hypercalcemia.These method and compositions can be used for treating MDS or alleviate its symptom, and hypercalcemia rare or that nothing is relevant.
In some aspects, method of the present invention comprises that discontinuity treats the vitamin D compounds of effective dose and randomly give one or more other active ingredients.The dosage of vitamin D compounds can be high dose, allows to give patient's high dose and can not cause hypercalcemia because give vitamin D compounds by method discontinuity of the present invention.Vitamin D compounds can be that any vitamin D compounds is unrestricted.In preferred embodiments, vitamin D compounds is active vitamin D compounds such as calcitriol.The treatment effective dose of vitamin D compounds can be between about 3-300 μ g/ days, or at any dosage range of the following stated.In certain embodiments, the administration of vitamin D compounds is no more than per three days once.In preferred embodiments, the vitamin D compounds administration is weekly approximately.The treatment effective dose of active vitamin D compounds is preferably between about 3-300 μ g/ days, more preferably between about 5-200 μ g/ days, more preferably between about 15-105 μ g/ days, more preferably between about 15-90 μ g/ days, more preferably between about 20-80 μ g/ days, more preferably between about 35-75 μ g/ days, more preferably between about 30-60 μ g/ days, even more preferably about 45 μ g.In certain embodiments, this treatment effective dose of vitamin D compounds reaches the vitamin D compounds plasma peak concentration safely at least about 0.5nM, more preferably 1-7nM, even more preferably 3-5nM.Though the inventive method can adopt any vitamin D compounds, preferred vitamin D compounds should be able to reach plasma peak concentration rapidly and disappear fast.
In other embodiments, the invention provides the method for the treatment of osteomyelodysplasia syndrome (MDS) or alleviating its symptom, this method comprises vitamin D compounds and one or more other active ingredients for the treatment of effective dose.The treatment effective dose of vitamin D compounds can be any dosage, unites one or more other active ingredients and can effectively treat MDS or alleviate its symptom.In certain embodiments, the treatment effective dose of vitamin D compounds is a high dose.Other active ingredient can be one or more somatomedin, as hemopoietic growth factor or cytokine; Immunomodulator; Cytotoxicity preparation such as antimetabolite, anti-microtubule medicine, alkanisation preparation, cisplatin formulations, anthracyclines, antibiotics preparation or topoisomerase enzyme inhibitor; Can influence the medicine of rna transcription; The derivant of vitamin A, E and K; The energy specificity is learned the medicine of target in conjunction with the MDS associated biomolecule; Signal transduction inhibitor; The cytoprotective preparation; Or arsenical.The example of hemopoietic growth factor or cytokine includes but not limited to: erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) and more specifically say the reorganization erythropoietin (r-HuEPO), and the reorganization methionyl human granulocyte stimulating factors (r-metHuG-CSF).In other embodiments, the invention provides the pharmaceutical composition that contains one or more vitamin D compounds and one or more other active ingredients.
In the method for the invention, vitamin D compounds and one or more other active ingredients can pharmaceutical compositions, single agent form or version administration, be used for the treatment of MDS or alleviate its symptom, these dosage forms contain a kind of vitamin D compounds, or its pharmaceutically suitable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, vitamin D compounds and one or more optional other active ingredient preparations can be ended in any pharmaceutical composition well known by persons skilled in the art.In certain embodiments, vitamin D compounds can oral formulations or intravenous formulations administration.Preferred oral formulations comprises spissated in advance Emulsion, and it contains one or more vitamin D compounds, lipophilic phase constituent and surfactant.In certain embodiments of the invention, treatment MDS or the chemical compound that alleviates its symptom comprise the vitamin D compounds for the treatment of effective dose, or its pharmaceutically suitable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, with the combination of one or more other active ingredients.
Method and composition of the present invention can be used for treating the patient, the MDS of preferred human patients or alleviate its symptom.Obviously, method of the present invention can be used for treating MDS or alleviates its symptom with the compositions that contains active vitamin D compounds such as calcitriol, can reduce as far as possible or avoid hypercalcemia simultaneously.
Brief description of drawings
Fig. 1 provides the plasma concentration as the calcitriol of time function.
Fig. 2 A-2C provides haemachrome concentration (g/dL) and the erythrocyte incoming frequency (by the blood transfusion unit) as time function of patient #1 (Fig. 2 A), patient #2 (Fig. 2 B) and patient #3 (Fig. 2 C).
Detailed Description Of The Invention
The invention provides treatment Myelodysplastic syndromes (MDS) or alleviate the method for its symptom and contain one or more vitamin D compounds, the composition of preferred active vitamin D compounds such as calcitriol can at utmost reduce or eliminate the danger that hypercalcinemia occurs simultaneously. Aspect some, give one or more vitamin D compounds and one or more other active ingredients of the present invention.
Definition
" active vitamin D compounds " refers to when giving the patient or having bioactive vitamin D compounds during with cells contacting. The biologically active of vitamin D compounds can adopt test described herein or well known to those skilled in the art to assess, if measure the immunity test (such as enzyme immunity test " ELISA ") of gene expression. Vitamin D compounds exists with several forms with different activities level in body. For example, the vitamin D compound can first hydroxylation in liver be 25-hydroxyl ostelin and part activation, then in kidney fully activation be 1 α, 25-dihydroxy ostelin, this thing is also referred to as " calcitriol ". And calcitriol is the main biologically active form of vitamin D in the human body, does not need in vivo further modification to use immediately.
" calcium index " refers to medicine is produced a kind of measurement of blood calcium reaction relative ability. At Bouillon etc., reported the example of this measurement among 1995, the Endocrine Reviews.16:200-7. Calcium index 1 is active corresponding to the relative blood calcium of calcitriol. Calcium index 0.01 is active corresponding to the blood calcium of calcitriol. Calcium index 0.5 is corresponding to the active only about half of medicine of the blood calcium of calcitriol. The calcium index of medicine may be different because of used test method, for example whether measured and irritated the absorption of small intestine calcium (ICA) or bone calcium migratory activity (BCM), see Hurwitz et al, 1967, J.Nutr.91:319-323 and Yamada et al, report among 1988, the Mol.Cell. Endocrinol.59:57-66.. The active the best of blood calcium is expressed as the blood calcium activity with respect to calcitriol relatively, and this is a kind of best features of vitamin D compounds.
" clinical hypercalcinemia " refers to one or more symptoms or the Signs of hypercalcinemia. The Early manifestation of hypercalcinemia comprises: weakness, headache, sleepy, nauseating, vomiting, mouth are done, constipation, myalgia, ostalgia or metallic taste. Late period, performance comprised: polydipsia, frequent micturition, lose weight, pancreatitis, keep in dark place, itch, renal insufficiency, aminopherase rising, hypertension, heart murmur, mental aberration, numbness, stupor and heterotopic calcification. Hypercalcinemia may be life-threatening in the vitamin D compounds administration, and Ying Yu avoids usually.
" pre-concentration Emulsion " refers to work as and polarizable medium such as water, and the preparation of emulsion can be provided during contact.Term " emulsion " refers to contain polarizable medium such as water and organic component, and including but not limited to hydrophobic is the colloidal dispersion of lipotropy organic component, comprises two kinds of conventional emulsions and submicron droplet emulsions.Term " submicron droplet emulsion " refers to that droplet that organic component colloidal dispersion wherein forms or granule average largest dimension are less than 1000 nanometers.
" hypercalcemia " refers to that blood calcium concentration is higher than normal level (though its normal value may be slightly different, this depends on used determination techniques).Though think that this concentration of " normally " is slightly different with determination techniques, this value of human body is higher than 10.5mg/dL and thinks hypercalcemia.Hypercalcemia can be divided into the 0-4 level.0 grade is lower than 10.6mg/dL corresponding to the blood calcium concentration value; 1 grade corresponding to blood calcium concentration value 10.6-11.5mg/dL; 2 grades corresponding to blood calcium concentration value 11.6-12.5mg/dL; 3 grades corresponding to blood calcium concentration value 12.6-13.5mg/dL; 4 grades corresponding to blood calcium concentration value＞13.5mg/dL.See United States Patent (USP) 6,521,608.
" coupling " refers to adopt more than one and treats preparation.Do not limit the sequencing that gives MDS patient treatment preparation when adopting " coupling " term.In relating to the scheme that gives second kind of MDS patient treatment preparation, first kind of treatment preparation can prior to, simultaneously, afterwards or repeat to give.For example, first kind of treatment preparation can be before second kind of treatment preparation gives when 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 weeks; Or first kind of treatment preparation can be after second kind of treatment preparation 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 12 give when all.
" isomeric compound " refers to have the chemical formula identical with another kind of chemical compound but the different chemical compound of structure." constitutional isomer " example of propanol is an isopropyl alcohol, and wherein these two kinds of chemical compounds have the same molecular formula but link position difference between the atom.An example of " stereoisomer " is " enantiomer ", and it is the mirror image chemical compound of another chemical compound.Another example of stereoisomer is a diastereomer, and it is the stereoisomer that contains an above chiral centre, but is not enantiomer.
" intermittent administration " refers to obtain vitamin D compounds blood high concentration periodically but the method for hypercalcemia do not take place.The discontinuity medication comprises that the dose that periodically gives the patient can reach the high level of one or more vitamin D compounds.The discontinuity administration can comprise, for example but be not restriction, give one or more vitamin D compounds be no more than per three days once, approximately per 4 days once, approximately per 5 days once, approximately per 6 days once, approximately weekly, approximately once, approximately once, approximately once, approximately per 4 weeks were once per 3 weeks per 2 weeks in per 9 days.Break time of administration sustainable one, two, three or all around, or one, two, three, four, five or June or longer.The intermittent administration scheme comprises and gives vitamin D compounds aforesaid more or less number of times, or continues long treatment time, depends on the pharmacokinetics and the pharmacodynamics of used pharmaceutical preparation.Those skilled in the art are understood that might need the regulating cycle dosage regimen, comprises that any cyclical administration scheme that gives the high dose vitamin D compounds and hypercalcemia do not take place all belongs in the scope of the invention.An example of dosage regimen can adopt United States Patent (USP) 6,521, the inventive method that provides in 608, and it is for referencial use that this patent content is included this paper in.
" metabolite " refers to certain material after body processing, the another kind of material that promptly produces after the metabolism.The example of a series of metabolites can be from overactivity form 1 α of vitamin D2,25-dihydroxy ostelin begins, it is the metabolite of 25-hydroxyl ostelin, and 25-hydroxyl ostelin is the metabolite of ergocalciferol (vitamin D2), and ergocalciferol is the metabolite of ergosterol.Another example of a series of metabolites can be from 1 α, 25-dihydroxy ostelin (calcitriol) beginning, it is the metabolite of 25-hydroxyl ostelin, and 25-hydroxyl ostelin is the metabolite of ostelin (vitamin D3), and ostelin is the metabolite of 7-dehydrocholesterol.Another example of a series of metabolites can be from tachysterol, and it is the metabolite of dihydrotachysterol, and dihydrotachysterol is the metabolite of 25-hydroxyl dihydrotachysterol.
" the non-blood calcium vitamin D compounds that rises " refers to compare with the calcitriol dosage of assessing with test well known to those skilled in the art, causes taking place the less vitamin D compounds of hypercalcemia tendency.This non-example that rises the blood calcium vitamin D compounds comprises: the congener of calcitriol, and as Ro23-7553 and Ro24-5531 (1 α, 25-dihydroxy-16-alkene-23-alkynes-26, the own fluorenyl fluoro of 27-ostelin) available from Hoffmann-LaRoche.Non-other example that rises the blood calcium vitamin D compounds can be at United States Patent (USP) 4,717, finds in 721, and it is for referencial use to fit into this paper in this patent.
" medicine preparation " refers to that it contains the compositions of pharmaceutically acceptable composition when using.
" pharmaceutical preparation " refers to one or more vitamin D compounds, or the combination of the active component of one or more vitamin D compounds and one or more non-vitamin D compounds (including but not limited to diphosphate).This pharmaceutical preparation also can be united with other active component and given, and for example, vitamin D compounds can be united with hemopoietic growth factor or cytokine and treated MDS.
" precursor " refers to the chemical compound of another chemical compound that can be through transforming into biologically active.The example of a series of precursors can be from ergosterol, it is the precursor of ergocalciferol (vitamin D2), ergocalciferol is the precursor of 25-hydroxyl ostelin, 25-hydroxyl ostelin is 1, the precursor of 25-dihydroxy ostelin, and ergocalciferol is overactivity form 1 α of vitamin D2, the precursor of 25-dihydroxy ostelin.Another example of a series of precursors can be from the 7-dehydrocholesterol, and it is the precursor of ostelin (vitamin D3), and ostelin is the precursor of 25-hydroxyl ostelin, and 25-hydroxyl ostelin is 1, the precursor of 25-dihydroxy ostelin (calcitriol).Another example of a series of precursors can be from tachysterol, and its precursor is a dihydrotachysterol, and the precursor of dihydrotachysterol is a 25-hydroxyl dihydrotachysterol.
" intractable " and " not reacting " refers to that one or more symptoms that its MDS is relevant can not fully be alleviated clinically with the patient of present available MDS treatment preparation for treating.General this patient suffers from serious and secular active disease, needs other to treat and alleviates the relevant symptom of MDS.
" concertedness " refers to that any two kinds or multiple medication combined treatment are more effective than indivedual effects of single medicine.Feasible one or more medicines that can use than low dosage of the joint synergy of medicine, and/or the less administration number of times of described medicine is treated MDS patient.Can use medicine, and/or give the less number of times of described medicine when treating MDS or alleviating its symptom, can reduce the effect that gives the xicity related of described medicine and can not reduce described medicine than low dosage.In addition, the synergism effect that can cause improving Drug therapy MDS or alleviate its symptom.At last, side effect or the ill effect of using any single therapy relevant can be avoided or reduce to the synergism of medicine coupling.
" patient " and " patient " is used interchangeably.Term " patient " this paper is used in reference to animal, and preferred mammal comprises non-human primate (as cattle, pig, horse, cat, Canis familiaris L., rat and mice) and primates (as monkey, as cynomolgus monkey and people), more preferably the people.
" medicine " refers to can be used for any medicine of preventing or treat MDS or alleviating its symptom.In certain embodiments, term " medicine " refers to one or more vitamin D compounds.In other embodiments, term " medicine " does not refer to vitamin D compounds.Medicine should be known useful, or or at present is used to prevent or stop development, generation or the deterioration of MDS, or alleviates its symptom.
" treatment effective dose " refers to obtain the amount of certain composition of ideal treatment or preventive effect, and for example, the blood level that can obtain vitamin D compounds is higher than the normal sufficiently long time and has therapeutic effect but do not have clinical xicity related dosage.The method according to this invention, the treatment effective dose scope of vitamin D compounds can be 3-300 μ g, or any scope wherein.It is relevant with the curative effect raising that the vitamin D compounds blood level reaches higher peak, but this curative effect of some time is subjected to toxic restriction.Specific dosage regimen makes and can give higher dosage safely and the hypercalcemia related symptoms can not take place.In concrete enforcement, vitamin D compounds (preferred active vitamin D compounds, or the non-calcium vitamin D compounds that rises) treatment effective dose is: 5,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,105,110,115,120,125,130,135,140,145,150,155,160,165,170,175,180,185,190,195,200,205,210,215,220,225,230,235,240,245,250,255,260,265,270,275,280,285,290,295 or 300 μ g, or higher.In reaching certain scheme in when point, the treatment effective dose of active vitamin D compounds is preferably between about 3-300 μ g/ days, more preferably between about 5-200 μ g/ days, more preferably between about 15-105 μ g/ days, more preferably between about 15-90 μ g/ days, more preferably between about 20-80 μ g/ days, more preferably between about 35-75 μ g/ days, more preferably between about 30-60 μ g/ days, even more preferably about 45 μ g.In certain embodiments, the peak serum concentration that the treatment effective dose of vitamin D compounds can reach vitamin D compounds safely is at least about 0.5nM, more preferably about 1-7nM, even more preferably about 3-5nM.
" treatment " and " processing " refers to give one or more preventions or curative drug before or after the generation of MDS symptom." treatment " and " processing " also comprises the time that the prolongation patient keeps alleviation, and/or MDS takes place the object that prevention is in the trouble MDS danger again." treatment " and " processing " also comprises prevention patient recurrence or one or more MDS symptoms takes place.The MDS related symptoms includes but not limited to: anemia, thrombocytopenia, neutrophilic leukocyte reduce, two cell reduces (two kinds of cell lines lack) and general cell lacks (three kinds of cell lines lack).
" vitamin D compounds " refers to vitamin D receptor (VDR) is had any kind of chemical compound of affinity.Vitamin D compounds of the present invention can concentrate in blood to the treatment effect level.VDR is a kind of transcription factor that is subjected to ligand activation, or intracellular receptor, can transcribe by starting in conjunction with the vitamin D response element in target gene promoters/enhancing subarea.Vitamin D compounds in the scope of the invention includes but not limited to: calcitriol, 1,25-dihydrocalciferol, calcifediol, 25-hydroxyl ostelin, vitamin D2, ostelin, 1 α HEC (doxercalciferol), dihydrotachysterol, paracalcitol and their derivant, congener, congener, precursor and metabolite.Preferred vitamin D compounds is an active vitamin D compounds, includes but not limited to: calcitriol and its all derivants, congener, congener, precursor and metabolite.Most preferred vitamin D compounds is a calcitriol.
Vitamin D compounds
In the method for the present invention, vitamin D compounds can be can be in conjunction with any chemical compound of vitamin D receptor, thereby can be the known any vitamin D compounds of art technology practician.For example, term " vitamin D " refers to ergocalciferol (vitamin D2) and ostelin (vitamin D3) traditionally, adopts any vitamin D compounds and derivant, congener, congener, precursor and metabolite but the present invention includes.Therefore, the term vitamin D compounds not only comprises the ergocalciferol and the ostelin of for example natural generation, also comprises their precursor ergosterol and 7-dehydrogenation ostelins separately.In addition, the term vitamin D compounds also comprises the activated form or the metabolite of ergocalciferol and ostelin, comprise 25-HEC and 25-hydroxyl ostelin (calcifediol), and overactivity form 1,25-dihydroxy ergocalciferol and 1,25-dihydroxy ostelin (calcitriol).
The structural formula of calcitriol is as follows:
Vitamin D compounds can separate acquisition from natural origin, or synthetic with the known method of these those skilled in the art.An example of synthesis of vitamin d congener is a dihydrotachysterol.Dihydrotachysterol is the synthetic property reduzate of tachysterol.Tachysterol is the precursor of vitamin D3,7-dehydrocholesterol, the side-product that forms during exposure.Dihydrotachysterol is active higher 10 times than its precursor tachysterol, is activated in liver even active higher 25-hydroxyl dihydrotachysterol.Other example of synthetic property vitamin D analogues is paracalcitol and 1 α HEC, and they can be used for reducing the level of parathyroid hormone.Another example of synthetic property vitamin D analogues is calcitriol (alfacalcidol), and it is at present in clinical treatment and prevention renal osteodystrophy, rickettsia, hypoparathyroidism and the osteoporosis of being used for of Canada.
Active vitamin D compounds
The used vitamin D compounds of the present invention comprises active vitamin D compounds.Be not subjected to the constraint of any particular theory or mechanism of action, vitamin D compounds becomes active, for example, be subjected to irradiation under ultraviolet ray to be transformed into vitamin D3 (ostelin) and (2) diet absorption vitamin D2 (ergocalciferol) or vitamin D3 (ostelin) by the 7-dehydrocholesterol in (1) skin.The two becomes vitamin D2 and vitamin D3 when activating through metabolism in liver and kidney target tissue is had complete activity.No matter vitamin D compounds is the transmutation product of skin ultraviolet radiation or takes in through diet that activatory next step may be to import a hydroxyl by the liver enzyme that is called CYP27 (vitamin D-2 5-hydroxylase) in the C-25 position of its side chain.At this moment, activatory vitamin D2 of part and D3 chemical compound are called 25-HEC and 25-hydroxyl ostelin respectively especially.The activatory chemical compound of these parts is activated fully by kidney 25-hydroxy-vitamin D-1-α-hydroxylase in the mitochondrion of nephridial tissue, produces 1 α of the main biologically active form of vitamin D2,25-(OH) 2High bioactivity form 1 α of D2 and vitamin D3,25-(OH) 2D3 (calcitriol).Activation vitamin D compounds of the present invention includes but not limited to: congener, congener and the derivant of vitamin D compounds described in the following patent (it is for referencial use to fit into this paper in it):
United States Patent (USP) 4,391,802 (1 α hydroxy-vitamine D derivants); 4,717,721 (its 17-side chain lengths is greater than 1 Alpha-hydroxy derivants of cholesterol or ergocalciferol side chain); 4,851,401 (Pentamethylene. base vitamin D analogues); 5,145,846 (the vitamin D3 congeners of band thiazolinyl, alkynyl and alkyl); 5,120,722 (trihydroxy calcitriols); 5,547,947 (fluoro ostelin chemical compounds); 5,446,035 (methyl substituted vitamin D); 5,411,949 (23-oxa derivants); 5,237,110 (19-nor--vitamin D compounds); 4,857,518 (hydroxylating 24-homovitamin D derivants).Other example of activation vitamin D compounds is listed in the following patent (it is for referencial use that each patent content is included this paper in): 6,503,893; 6,482,812; 6,441,207; 6,410,523; 6,399,797; 6,392,071; 6,376,480; 6,372,926; 6,372,731; 6,359,152; 6,329,357; 6,326,503; 6,310,226; , 6,288,249; 6,281,249; 6,277,837; 6,218,430; 6,207,656; 6,197,982; 6,127,559; 6,103,709; 6,080,878; 6,075,015; 6,072,062; 6,043,385; 6,017,908; 6,017,907; 6,013,814; 5,994,332; 5,976,784; 5,972,917; 5,945,410; 5,939,406; 5,936,105; 5,932,565; 5,929,056; 5,919,986; 5,905,074; 5,883,271; 5,880,113; 5,877,168; 5,872,140; 5,847,173; 5,843,927; 5,840,938; 5,830,885; 5,824,811; 5,811,562; 5,786,347; 5,767,111; 5,756,733; 5,716,945; 5,710,142; 5,700,791; 5,665,716; 5,663,157; 5,637,742; 5,612,325; 5,589,471; 5,585,368; 5,583,125; 5,565,589; 5,565,442; 5,554,599; 5,545,633; 5,532,228; 5,508,392; 5,508,274; 5,478,955; 5,457,217; 5,447,924; 5,446,034; 5,414,098; 5,403,940; 5,397,775; 5,395,830; 5,393,749; 5,384,313; 5,374,629; 5,373,004; 5,371,249; 5,321,018; 5,281,731; 5,260,290; 5,254,538; 5,250,523; 5,247,104; 5,246,925; 5,232,836; 5,194,431; 5,185,150; 5,086,191; 5,036,061; 5,030,772; 4,973,584; 5,354,744; 4,940,700; 4,927,815; 4,866,048; 4,851,400; 4,847,012; 4,804,502; 4,769,181; 4,755,329; 4,719,205; 4,719,204; 4,619,920; 4,594,192; 4,588,716; 4,588,528; 4,564,474; 4,552,698; 4,689,180; 4,505,906; 4,502,991; 4,481,198; 4,448,726; 4,448,721; 4,428,946; 4,411,833; 4,367,177; 4,360,472; 4,360,471; 4,358,406; 4.336.193; 4,307,231; 4,307,025; 4,305,880; 4,279,826; With 4,248,791.The more fully list of active vitamin D compounds can find at the PCT application WO 99/49870 that publishes, and it is for referencial use to fit into this paper in it.
Other clinical used active vitamin D compounds includes but not limited to: the medicine of Leo Pharmaceutical research, and as EB 1089 (24a, 26a, 27a-three-hypers-22,24-diene-1 α a, 25-(OH) 2-D3), KH 1060 (20-g table-22-oxa--24a, 26a, 27a-three-hypers-1 α, 25-(OH) 2D3), MC 1288 and MC 903 (calcitriol); The medicine of Roche Pharmaceutical as: 1,25-(OH) 2-16-alkene-D3,1,25-(OH) 2-16-alkene-23-alkynes-D3 and 25-(OH) 2-16-alkene-23-alkynes-D3; Chugai Pharmaceuticals such as 22-oxa-calcitriol (22-oxa--1 α, 25-(OH) 2-D3); Illionis university is as 1 α (OH) D5; With MedicalChemistry-Schering AG institute such as ZK 161422 (20-methyl isophthalic acid, 25-(OH) 2-D3) and ZK 157202 (20-methyl-23-alkene-1,25-(OH) 2-D3).Vitamin D analogues also comprises local application's goods of vitamin D compounds, as calcipotriene
Figure C20038010737900221
Tacalcitol Specifically can be from the active vitamin D compounds preparation of commercial acquisition It can obtain from Roche; With
Figure C20038010737900224
It can obtain from Abbott.
Other example of active vitamin D compounds and their derivant, congener, congener, precursor and metabolite includes but not limited to: 1 α, 25-(OH) 2-26,27-d 6-D3,1 α, 25-(OH) 2-22-alkene-D3,1 α-(OH) 2-D3,
1α，25-(OH) 2-D2、1α，25-(OH) 2-D4、1α，24，25-(OH) 3-D3、1α，24，25-(OH) 3-D2、
1α，24，25-(OH) 3-D4、1α-(OH)-25-FD3、1α-(OH)-25-FD4、1α-(OH)-25-FD2、
1α，24-(OH) 2-D4、1α，24-(OH) 2-D3、1α，24-(OH) 2-D2、1α，24-(OH) 2-25-FD4、
1 α, 24-(OH) 2-25-FD3,1 α, 24-(OH) 2-25-FD2,1 α, 25-(OH) 2-26,27-F 6-22-alkene-D3,
1α，25-(OH) 2-26，27-F 6-D3、1α，25S-(OH) 2-26-F 3-D3、1α，25-(OH) 2-24-F 2-D3、
1 α, 25S, 26-(OH) 2-22-alkene-D3,1 α, 25R, 26-(OH) 2-22-alkene-D3,1 α, 25-(OH) 2-D2,
1 α, 25-(OH) 2-24-table-D3,1 α, 25-(OH) 2-23-alkynes-D3,1 α, 25-(OH) 2-24R-F-D3,
1 α, 25S, 26-(OH) 2-D3,1 α, 24R-(OH) 2-25F-D3,1 α, 25-(OH) 2-26,27-F 6-23-alkynes-D3,
1 α, 25-(OH) 2-26-F 3-D3,1 α, 25,28-(OH) 3-D2,1 α, 25-(OH) 2-16-alkene-23-alkynes-D3,
1 α, 24R, 25-(OH) 3-D3,1 α, 25-(OH) 2-26,27-F 6-alkene-D3,
1 α, 25R-(OH) 2-22-alkene-26-F 3-D3,1 α, 25S-(OH) 2-22-alkene-26-F 3-D3,
1α，25R-(OH) 2-D3-26，26，26-D3、1α，25S-(OH) 2-D3-26，26，26-D3
With 1 α, 25R-(OH) 2-22-alkene-D3-26,26,26-D3.
In addition, though the inventive method can adopt vitamin D compounds, preferred vitamin D compounds has the pharmacokinetics performance, makes them be more suitable for following method than other vitamin D compounds.Usually, preferred vitamin D compounds can make plasma concentration reach peak value in about 4 hours rapidly, and disappeared fast, as eliminate about 12 hours of half-life or less than.The elimination half-life is meant that the said preparation plasma concentration reduces by 50% time, and disappearance herein means that plasma concentration is lower than about 0.5nM.Though inequality between the plasma concentration patient of endogenous vitamin D, they are about 0.16nM normally.Calcitriol is an example with preferred vitamin D chemical compound of above-mentioned ideal medicament dynamic performance.Though do not want to be subjected to the constraint of any particular theory or mechanism of action, but it is believed that the vitamin D compounds with these pharmacokinetics performances is when the concentration that short-term raises, can cause the therapeutic biologically, drop to fast then below the threshold concentration value that helps calcium release, thereby at utmost reduce hypercalcemia.
In the preferred embodiment of the invention, active vitamin D compounds is a calcitriol.
The non-vitamin D compounds that rises blood calcium
The used vitamin D compounds of the present invention also comprises the non-blood calcium vitamin D compounds that rises.Yet in certain embodiments of the invention, vitamin D compounds is not the non-blood calcium vitamin D compounds that rises.As the measurement of test method of knowing with these those skilled in the art, the non-blood calcium vitamin D compounds that rises causes that the tendency of hypercalcemia generation is lower than equal dose calcitriol.
The non-example that rises the blood calcium vitamin D compounds of this class comprises: the congener of calcitriol, and as Ro23-7553 and Ro24-5531 (1 α, 25-dihydroxy-16-alkene-23-alkynes-26,27-hexafluoro cholecalciferol) available from Hoffmann-LaRoche.Non-other example that rises the blood calcium vitamin D compounds can be at United States Patent (USP) 4,717, finds in 721, and it is for referencial use to fit into this paper in it.
Said vitamin D chemical compound is not every, just can be in conjunction with the example of all chemical compounds of VDR.The technical staff understands and the present invention includes all vitamin D compounds, promptly all can be in conjunction with the chemical compound of VDR, and derivant, congener, congener, precursor, metabolite and pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug.
Other treats preparation
In some aspects, the present invention provides the compositions for the treatment of MDS or alleviating its one or more symptoms by giving vitamin D compounds and one or more other active ingredients.Described other preparation can be to have treatment MDS or alleviate any active medicine of its symptom curative effect, and this is to those skilled in the art will know that and unrestricted.Described active ingredient includes but not limited to: micromolecule, synthetic drug, peptide, polypeptide, protein, nucleic acid (as DNA and RNA nucleotide, including but not limited to the nucleotide sequence of antisense base sequences, triple helical and encoding human reactive protein, polypeptide or peptide), antibody, synthetic or natural inorganic molecule, aids drug and synthetic or natural organic molecule.Any known useful or that adopted or present the treating MDS or alleviate the medicine of one or more relevant symptoms of MDS of usefulness, all can with vitamin D compounds coupling of the present invention.
In certain embodiments, compositions of the present invention comprises and gives other active medicine that vitamin D compounds of the present invention and one or more have associating, collaborative, adjection or other therapeutic effect.In one embodiment, vitamin D compounds of the present invention can with somatomedin, give together as cytokine or hemopoietic growth factor.In another embodiment, vitamin D compounds of the present invention can give with immunomodulator.In also having an embodiment, vitamin D compounds of the present invention can give with cytotoxic drug.In also having an embodiment, vitamin D compounds of the present invention can give with the medicine that can influence rna transcription.In also having an embodiment, vitamin D compounds of the present invention can give with the derivant of vitamin A, E or K.In also having an embodiment, vitamin D compounds of the present invention can give with the medicine of energy specificity in conjunction with MDS associated biomolecule target.In also having an embodiment, vitamin D compounds of the present invention can give with signal transduction inhibitor.In also having an embodiment, vitamin D compounds of the present invention can give with amineothiot.In also having an embodiment, vitamin D compounds of the present invention can give with arsenical.Other embodiment of the present invention comprises the above-mentioned active ingredient that gives vitamin D compounds of the present invention and more than one.
Somatomedin or cytokine
In one embodiment of this invention, vitamin D compounds of the present invention can give with somatomedin.Any somatomedin that can effectively treat MDS or alleviate its symptom well known by persons skilled in the art all can need the patient of this treatment with vitamin D compounds.In another embodiment of the present invention, one or more somatomedin that can effectively treat MDS or alleviate its symptom well known by persons skilled in the art can give with vitamin D compounds and above-mentioned one or more other active ingredients.
Can be used for the example that various embodiments of the present invention are included in the somatomedin in pharmaceutical composition, dosage form and the test kit, include but not limited to: cytokine or hemopoietic growth factor, as EPO, TPO, GM-CSF, G-CSF, IFN-α, IL-1, IL-2, IL-3, IL-6, IL-8, IL-11 and IL-12.In addition, above-mentioned cytokine or hemopoietic growth factor reorganization, that modify, mimic, fragmentation or of the same type also can be used in the various embodiments of the present invention.See United States Patent (USP) 6,358,505; 6,346,531; 6,340,742; 6,262,253; 6,261,550; 6,166,183; 6,100,070; 5,986,047; 5,981,551; 5,916,773; 5,902,584; 5,835,382; 5,824,778; 5,773,581; 5,773,569 and 5,756,349, these patents state all reorganization, that modify, mimic, fragmentation or of the same type EPO and G-CSF, it is for referencial use to fit into this paper in them.Preferred cytokine or hemopoietic growth factor comprise r-HuEPO and r-metHuG-CSF.
The r-HuEPO of commercialization form is
Figure C20038010737900251
It is produced by recombinant DNA technology, has biological effect identical with the endogenous erythropoietin and identical aminoacid sequence.1ml
Figure C20038010737900252
In dosage contain erythropoietin-α, 2.5mg albumin (people), the 1.2mg sodium dihydrogen phosphate H of 2000,3000,4000 or 10,000 units 2O, 1.8mg disodium hydrogen phosphate,anhydrous, 0.7mg sodium citrate, 5.8mg sodium chloride, 6.8mg citric acid and water are used for injection, USP (pH6.9 ± 0.3).Can obtain the multi-agent form
Figure C20038010737900253
All dosage forms all are contained in the bottle of gastrointestinal tract external administration.See Physician ' Desk Reference 582 (the 56th edition, 2002).
An example that is also referred to as the r-metHuG-CSF commercialization form of filgrastim is It is produced in escherichia coli with recombinant DNA technology, and separates that G-CSF from people's cell is different to be that it is not by glycosylation.1ml
Figure C20038010737900255
In dosage contain 300 μ g filgrastim, 0.59mg acetate, 50.0mg sorbitol, 0.004% Tween 80,0.035mg sodium and 1.0ml water, be used for the injection, USP.Can obtain heavy dose of
Figure C20038010737900256
Being contained in gastrointestinal tract gives in the red bottle outward.See Physician ' DeskReference 588 (the 56th edition, 2002).
Immunomodulator
In another embodiment of the present invention, vitamin D compounds of the present invention can give with immunomodulator.Immunomodulator can be the known any immunomodulators that can effectively treat MDS or alleviate its symptom of those skilled in the art.In another embodiment of the present invention, known one or more immunomodulators that can effectively treat MDS or alleviate its symptom of those skilled in the art can give the patient with vitamin D compounds and one or more other active medicines described herein.
Be packaged in the example of the immunomodulator that can be used for the various embodiments of the present invention in pharmaceutical composition of the present invention, dosage form and the test kit, include but not limited to: antithymocyte globulin (ATG), antilymphocyte globulin (ALG), thalidomide (thalidomide), prednisone, cyclosporin A (CyA), dexamethasone and pentoxifylline (pentoxifylline).
The cytotoxicity preparation
In another embodiment of the present invention, vitamin D compounds of the present invention can give with the cytotoxicity preparation.The agent of cytotoxicity preparation can be the known any cytotoxicity preparations that can effectively treat MDS or alleviate its symptom of those skilled in the art.In another embodiment of the present invention, known one or more cytotoxicity preparations that can effectively treat MDS or alleviate its symptom of those skilled in the art can give the patient with vitamin D compounds and one or more other active medicines described herein.
Method of the present invention can adopt the cytotoxicity preparation, the many cytotoxicity preparations that are fit to MDS or cancer chemotherapeutic generally are that this area is known, for example, the cytotoxicity preparation can be that antimetabolite is (as 5-fluorouracil (5-FU), methotrexate (MTX), fluorine draws and reaches shore (fludarabine) etc.), anti-microtubule medicine is (as vincristine, vinblastine, taxanes such as paclitaxel and Duo Xi Ramulus et folium taxi cuspidatae etc.), alkylating agent is (as cyclophosphamide, melphalan, carmustine etc.), platinum class preparation is (as cisplatin, carboplatin, JM-216, JM-216, CI-973 etc.), anthracyline is (as amycin, daunorubicin etc.), antibiotic formulations is (as Mitomycin-C, actinomycin D etc.), topoisomerase enzyme inhibitor is (as etoposide, camptothecine etc.) or other cytotoxicity preparation.
Be packaged in the example of the cytotoxicity preparation that can be used for the various embodiments of the present invention in pharmaceutical composition of the present invention, dosage form and the test kit, include but not limited to: cytosine arabinoside, melphalan, topotecan, fludarabine, etoposide, O-Demethyldaunomycin, daunorubicin, mitoxantrone, cisplatin, paclitaxel and cyclophosphamide.
Other medicine of MDS
In another embodiment of the present invention, vitamin D compounds of the present invention can give with the medicine that can influence rna transcription.Can to be that those skilled in the art are known can effectively treat MDS or alleviate any medicine in the medicine that can influence rna transcription of its symptom the medicine that can influence rna transcription.In another embodiment of the present invention, those skilled in the art are known can effectively treat MDS or alleviate its symptom one or more can influence the medicine of rna transcription, can give the patient with vitamin D compounds and one or more other active medicines described herein.The non-limitative example that can influence the rna transcription medicine that can be used in the various embodiments of the present invention that is packaged in pharmaceutical composition of the present invention, dosage form and the test kit comprises: decitabing, 5-azacytidine, depside peptide (depsipeptides) and phenyl butyrate.
In another embodiment of the present invention, vitamin D compounds of the present invention can give with the derivant of vitamin A, E or K.The derivant of vitamin A, E or K can be the known any derivants that can effectively treat MDS or alleviate vitamin A, E or the K of its symptom of those skilled in the art.In another embodiment of the present invention, the known derivant that can effectively treat MDS or alleviate one or more vitamin A, E or the K of its symptom of those skilled in the art can give the patient with vitamin D compounds and one or more other active medicines described herein.The non-limitative example that is packaged in the vitamin A that can be used for the various embodiments of the present invention, E or K derivant in pharmaceutical composition of the present invention, dosage form and the test kit comprises: all trans retinoic acid, 13-are suitable-and tretinoin, tocopherol and Menaquinone K6 (menatetrenone).
In another embodiment of the present invention, vitamin D compounds of the present invention can give with the medicine of energy specificity in conjunction with MDS associated biomolecule target.Can specificity in conjunction with the medicine of MDS associated biomolecule target can be those skilled in the art known can effectively treat MDS or alleviate its symptom can specificity in conjunction with any medicine of MDS associated biomolecule target.In another embodiment of the present invention, those skilled in the art are known effectively to be treated MDS or alleviate the medicine of one or more energy specificitys of its symptom in conjunction with the relevant target of MDS, can give the patient with vitamin D compounds and one or more other active medicines described herein.Be packaged in and can be used for can specificity comprising of the various embodiments of the present invention in pharmaceutical composition of the present invention, dosage form and the test kit: anti-VEGF, gemtuzumab ozogamicin and TNFR:Fc in conjunction with the non-limitative example of the relevant target agent of MDS.
In another embodiment of the present invention, vitamin D compounds of the present invention can give with signal transduction inhibitor.Signal transduction inhibitor can be the known any signal transduction inhibitors that can effectively treat MDS or alleviate its symptom of those skilled in the art.In another embodiment of the present invention, known one or more signal transduction inhibitors that can effectively treat MDS or alleviate its symptom of those skilled in the art can give the patient with vitamin D compounds and one or more other active medicines described herein.The non-limitative example that is included in the signal transduction inhibitor that can be used for the various embodiments of the present invention in pharmaceutical composition of the present invention, dosage form and the test kit comprises: method Buddhist nun's inhibitors such as Zarnestra TMAnd Sarasar TMWith tyrosine kinase inhibitor such as SU5416, SU6668 and PTK787/ZK222584.
In another embodiment of the present invention, vitamin D compounds of the present invention can give with amineothiot (aminothiol).Amineothiot can be the known any amineothiots that can effectively treat MDS or alleviate its symptom of those skilled in the art.In another embodiment of the present invention, one or more amineothiots that those skilled in the art are known effectively to be treated MDS or alleviate its symptom can give the patient with vitamin D compounds and one or more other active medicines described herein.The amineothiot that can be used for the various embodiments of the present invention that is included in pharmaceutical composition of the present invention, dosage form and the test kit is Amifostine (amifostine).
In another embodiment of the present invention, vitamin D compounds of the present invention can give with arsenical.Can to be that those skilled in the art are known can effectively treat MDS or alleviate any arsenical in the medicine that can influence rna transcription of its symptom arsenical.In another embodiment of the present invention, one or more arsenicals that can effectively treat MDS or alleviate its symptom well known by persons skilled in the art can give the patient with vitamin D compounds and one or more other active medicines described herein.The arsenical that can be used for the various embodiments of the present invention that is included in pharmaceutical composition of the present invention, dosage form and the test kit is an arsenic trioxide.
The method of treatment osteomyelodysplasia syndrome.
The present invention provides the method for the treatment of MDS or alleviating its symptom to the patient of needs treatment or mitigation symptoms.Also to once accepting the MDS treatment, and the patient who never accepted the MDS treatment provides treatment this sick method.Because MDS patient's clinical manifestation is different, clinical final result is also different, therefore prognosis and the Therapeutic Method that must prepare the patient according to the order of severity of disease and stage.Really, method of the present invention can be used for being in patient's the treatment of one or more types of trouble MDS of different phase, and include but not limited to: refractory anemia (RA), band form high ferro small cell refractory anemia (RARS).In addition, method of the present invention can be used for being in patient's the treatment of one or more types of trouble MDS of different phase, includes but not limited to: the MDS of low danger, meta-1 phase danger, medium-2 phases danger or high-risk.
Method provided by the invention is the vitamin D compounds for the treatment of effective dose, at utmost reduces the danger that hypercalcemia takes place simultaneously when treating the osteomyelodysplasia syndrome or alleviating its symptom.In certain embodiments, this method comprises that the vitamin D compounds for the treatment of effective dose treats MDS or alleviate its symptom.In other embodiments, this method comprises that discontinuity gives the vitamin D compounds of high dose.Discontinuity gives vitamin D compounds and can allow to give the high dosage of patient and can at utmost reduce or eliminate hypercalcemia simultaneously.In also having other embodiment, this method comprises employing oral vitamin D compound formulation.Also in other embodiments, this method comprises the oral stable vitamin D compounds preparation that adopts the improved vitamin D compounds of bioavailability can reach the blood peak level rapidly.In other embodiments, this method comprises and adopts the oral vitamin D chemical compound of concentrated emulsion form in advance.In other embodiments, this method comprises the vitamin D compounds preparation that adopts intravenous injection (i.v).In certain embodiments, vitamin D compounds gives with single therapy.In other embodiments, vitamin D compounds and preparation give with one or more other active medicines.In also having other embodiment, vitamin D compounds and preparation give with one or more hemopoietic growth factors or cytokine.
In certain embodiments, method of the present invention comprises that the vitamin D compounds for the treatment of effective dose treats the osteomyelodysplasia syndrome or alleviate its symptom, at utmost reduces the danger that hypercalcemia takes place simultaneously.In certain embodiments, method of the present invention comprises that the vitamin D compounds for the treatment of effective dose treats the anemia relevant with MDS.In other embodiments, method of the present invention comprises that the vitamin D compounds for the treatment of effective dose improves MDS patient's haemachrome blood plasma level.In also having other embodiment, method of the present invention comprises that the vitamin D compounds for the treatment of effective dose reduces MDS patient's blood transfusion demand.In other embodiments, method of the present invention comprises that the vitamin D compounds for the treatment of effective dose treats the relevant thrombocytopenia of MDS.In other embodiments, method of the present invention comprises that the vitamin D compounds for the treatment of effective dose reduces the MDS mortality in said patients.In other embodiments, method of the present invention comprises that the vitamin D compounds for the treatment of effective dose reduces the patient and dampens number of times and the seriousness that bruise takes place.In other embodiments, method of the present invention comprises that the vitamin D compounds for the treatment of effective dose comes MDS patient's times of bleeding and seriousness.In other embodiments, method of the present invention comprises that the vitamin D compounds for the treatment of effective dose reduces MDS patient's heating number of times and seriousness.In other embodiments, method of the present invention comprises that the vitamin D compounds for the treatment of effective dose treats the relevant neutrophilic leukocyte of MDS and reduce.In other embodiments, method of the present invention comprises that the vitamin D compounds for the treatment of effective dose reduces MDS patient's infection frequency and seriousness.In other embodiments, method of the present invention comprises that the MDS that the vitamin D compounds for the treatment of effective dose delays MDS patient develops to leukemia.Also in other embodiments, method of the present invention comprises that the vitamin D compounds for the treatment of effective dose prolongs MDS patient's life span.
Be not subjected to the constraint of any particular theory or mechanism of action, it is believed that vitamin D compounds and the effective medicine of other treatment MDS treating MDS or alleviating in its symptom, can work with complementation or cooperative mode.Therefore, an embodiment that comprises treatment MDS or alleviate its symptom of the present invention, comprise that the patient who needs this treatment and/or mitigation symptoms is to treat the vitamin D compounds of effective dose, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, and one or more other active medicines as herein described of treatment effective dose.
One skilled in the art will appreciate that the patient's that also can adopt any Therapeutic Method as herein described to prevent this prevention of needs MDS outbreak or recurrence.
The administration and the dosage of vitamin D compounds in the treatment osteomyelodysplasia syndrome
Give the vitamin D compounds of the inventive method by discontinuity, can realize the general high level of vitamin D compounds and hypercalcemia does not take place.The vitamin D compounds of high dose comprises the dosage greater than about 3 μ g described in the following chapters and sections.Therefore, in certain embodiments of the invention, treatment MDS or the method that alleviates its symptom comprise that discontinuity gives the vitamin D compounds of high dose.The vitamin D compounds of high dose can be taken turns other therapies in the treatment every, includes but not limited to before the drug therapy, simultaneously or give afterwards.Also can take turns and give vitamin D compounds in the therapeutic scheme, for example can take turns in the scheme, or in the serial therapy round, before the other therapies, simultaneously or give vitamin D compounds afterwards any one at each.The number of times of intermittent administration may be subjected to the influence of many factors, includes but not limited to the pharmacokinetic parameter of chemical compound or preparation, and vitamin D compounds is to patient's drug effect.For example, there have the MDS patient of renal dysfunction may need to give the number of times of vitamin D compounds to be less, reduces because these patients drain the ability of calcium.
Just in order to illustrate, term " discontinuity " can comprise the designed any dosage regimen of this field those of ordinary skill individual to following demonstration example.
In one embodiment, can give vitamin D compounds was no more than once in per three days.Sustainable 1,2,3 or 4 weeks of administration or 1,2,3,4,5 or June or 1 year or longer.In certain embodiments, can give vitamin D compounds alleviates up to the relevant anemia of MDS.Randomly, after rest a period of time, can identical or different scheme give vitamin D compounds.Time of having a rest can be 1,2,, 3 or 4 weeks or longer, according to vitamin D compounds patient's drug effect is decided.
In another embodiment, sustainable administration 1,2,3 or 4 weeks or 1,2,3,4,5 or June or 1 year or longer.In certain embodiments, can give vitamin D compounds alleviates up to the relevant anemia of MDS.Randomly, after rest a period of time, can identical or different scheme give vitamin D compounds.Time of having a rest can be 1,2,, 3 or 4 weeks or longer, according to vitamin D compounds patient's drug effect is decided.
In another embodiment, can give vitamin D compounds was no more than once in per five days.Administration sustainable 1,2,3 or 4 the week 1,2,3,4,5 or June or 1 year longer.In certain embodiments, can give vitamin D compounds alleviates up to the relevant anemia of MDS.Randomly, after rest a period of time, can identical or different scheme give vitamin D compounds.Time of having a rest can be 1,2,, 3 or 4 weeks or longer, according to vitamin D compounds patient's drug effect is decided.
In another embodiment, can give vitamin D compounds was no more than once in per six days.Sustainable 1,2,3 or 4 weeks of administration or 1,2,3,4,5 or June or 1 year or longer.In certain embodiments, can give vitamin D compounds alleviates up to the relevant anemia of MDS.Randomly, after rest a period of time, can identical or different scheme give vitamin D compounds.Time of having a rest can be 1,2,, 3 or 4 weeks or longer, according to vitamin D compounds patient's drug effect is decided.
In another embodiment, can give vitamin D compounds was no more than once in per 7 days.Sustainable 1,2,3 or 4 weeks of administration or 1,2,3,4,5 or June or 1 year or longer.In certain embodiments, can give vitamin D compounds alleviates up to the relevant anemia of MDS.Randomly, after rest a period of time, can identical or different scheme give vitamin D compounds.Time of having a rest can be 1,2,, 3 or 4 weeks or longer, according to vitamin D compounds patient's drug effect is decided.
In another embodiment, can give vitamin D compounds was no more than once in per 8 days.Sustainable 1,2,3 or 4 weeks of administration or 1,2,3,4,5 or June or 1 year or longer.In certain embodiments, can give vitamin D compounds alleviates up to the relevant anemia of MDS.Randomly, after rest a period of time, can identical or different scheme give vitamin D compounds.Time of having a rest can be 1,2,, 3 or 4 weeks or longer, according to vitamin D compounds patient's drug effect is decided.
In another embodiment, can give vitamin D compounds was no more than once in per 9 days.Sustainable 1,2,3 or 4 weeks of administration or 1,2,3,4,5 or June or 1 year or longer.In certain embodiments, can give vitamin D compounds alleviates up to the relevant anemia of MDS.Randomly, after rest a period of time, can identical or different scheme give vitamin D compounds.Time of having a rest can be 1,2,, 3 or 4 weeks or longer, according to vitamin D compounds patient's drug effect is decided.
In another embodiment, can give vitamin D compounds was no more than once in per 10 days.Sustainable 1,2,3 or 4 weeks of administration or 1,2,3,4,5 or June or 1 year or longer.In certain embodiments, can give vitamin D compounds alleviates up to the relevant anemia of MDS.Randomly, after rest a period of time, can identical or different scheme give vitamin D compounds.Time of having a rest can be 1,2,, 3 or 4 weeks or longer, according to vitamin D compounds patient's drug effect is decided.
In another embodiment, can give vitamin D compounds three totally months once in a week.Randomly, after rest a period of time, can identical or different scheme give vitamin D compounds.Time of having a rest can be 1,2,, 3 or 4 weeks or longer, according to vitamin D compounds patient's drug effect is decided.
In another embodiment, can give once totally one year per three weeks of vitamin D compounds.Randomly, after rest a period of time, can identical or different scheme give vitamin D compounds.Time of having a rest can be 1,2,, 3 or 4 weeks or longer, according to vitamin D compounds patient's drug effect is decided.
In a preferred embodiment, can give vitamin D compounds totally three weeks once in a week, per 4 Mondays wheel.Have a rest after the week, can identical or different scheme give vitamin D compounds.
United States Patent (USP) 6,521 provides other example of the dosage that can be used in the inventive method in 608, and it is for referencial use to fit into this paper in this patent.
Provide above-mentioned dosage regimen purpose just to illustrate and should not think restriction.Those of ordinary skills are understood that all vitamin D compounds all within the scope of the invention; Preferred calcitriol ex hoc genus anne thing, congener, derivant, precursor and metabolite; The definite dosage that gives vitamin D compounds can be different owing to many factors with scheme.
The treatment effective dose of medicine and preparation may be different when the acute or chronic processing of disease, and this depends on many factors, includes but not limited to: disease of being treated or disease, concrete pharmaceutical preparation and route of administration.The method according to this invention, the treatment effective dose of vitamin D compounds are any dosage that can effectively treat MDS or alleviate the vitamin D compounds of its symptom.The vitamin D compounds of high dose can be about 3-300 μ g dosage, or as following any dosage in this scope.Dosage, administration number of times, persistent period or any combination also can be because of patient's age, body weight, reaction and previously the pharmacokinetics of medical history and route of administration, this pharmaceutical preparation is different with pharmacodynamic action.These those skilled in the art of these factors can do conventional consideration.
The absorption of vitamin D compounds and removing speed are subjected to the various factors influence that this field those of ordinary skill is known.As mentioned above, the pharmacokinetic properties of vitamin D compounds can limit its accessible peak concentration and do not cause the generation hypercalcemia in blood, and preference does not cause clinical hypercalcemia takes place.Absorption, distribution, combination or locating speed and the degree of vitamin D compounds in tissue, biotransformation and excretory speed and degree may all can have influence on the frequency that gives pharmaceutical preparation.In certain embodiments, by above-mentioned dosage, be interrupted the vitamin D compounds that gives high dose, as treatment MDS or alleviate the method for its symptom.
In certain embodiments of the invention, this method comprises and gives vitamin D compounds, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate, or prodrug, dosage is about 3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50,55,60,65,70,75,80,85,90,95,100,105,110,115,120,125,130,135,140,145,150,155,160,165,170,175,180,185,190,195,200,205,210,215,220,225,230,235,240,245,250,255,260,265,270,275,280,285,290,295 or 300 μ g, or any dosage in this scope.In some embodiment, method of the present invention comprises the vitamin D compounds that gives about 0.12 μ g/kg-3 μ g/kg dosage, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug.In other embodiments, method of the present invention comprises the vitamin D compounds that gives every dose of about 3-300 μ g, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug.In also having other embodiment, method of the present invention comprises the vitamin D compounds that gives every dose of about 5-200 μ g, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug.In also having other embodiment, method of the present invention comprises the vitamin D compounds that gives every dose of about 5-105 μ g, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug.In also having other embodiment, method of the present invention comprises the vitamin D compounds that gives every dose of about 15-105 μ g, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug.In also having other embodiment, method of the present invention comprises the vitamin D compounds that gives every dose of about 15-90 μ g, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug.In also having other embodiment, method of the present invention comprises the vitamin D compounds that gives every dose of about 20-80 μ g, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug.In also having other embodiment, method of the present invention comprises the vitamin D compounds that gives every dose of about 30-60 μ g, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug.In also having other embodiment, method of the present invention comprises the vitamin D compounds that gives every dose of about 30-75 μ g, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug.In the preference embodiment, method of the present invention comprises the vitamin D compounds that gives every dose of about 45 μ g, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug.Those skilled in the art will know that these are standard doses of the about 70kg adult of average weight, and the factor that visual above-mentioned routine will be considered adjusts.Though do not want to be subjected to the constraint of any particular theory or mechanism of action, it is believed that the half-life that yet can not improve vitamin D compounds when dosage that vitamin D compounds gives is up to 105 μ g greatly and xicity related.Therefore, in a preferred embodiment, the dosage of vitamin D compounds is 105 μ g or less.
In certain embodiments, method of the present invention comprises and gives vitamin D compounds, or the dosage of its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, can make the about 0.1nM of the plasma concentration value of peaking, 0.2nM, 0.3nM, 0.4nM, 0.5nM, 0.6nM, 0.7nM, 0.8nM, 0.9nM, 1nM, 2nM, 3nM, 4nM, 5nM, 6nM, 7nM, 8nM, 9nM, 10mM, 12nM, 15nM, 17nM or the 20nM of vitamin D compounds, or any concentration in this scope.In other embodiments, method of the present invention comprises and gives vitamin D compounds, or the dosage of its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, can make the plasma concentration of vitamin D compounds surpass 0.5nM.In other embodiments, method of the present invention comprises and gives vitamin D compounds, or the dosage of its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, can make the plasma concentration of vitamin D compounds reach about 0.5-20nM.In other embodiments, method of the present invention comprises and gives vitamin D compounds, or the dosage of its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, can make the plasma concentration of vitamin D compounds reach about 1-10nM.In other embodiments, method of the present invention comprises and gives vitamin D compounds, or the dosage of its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, can make the plasma concentration of vitamin D compounds reach about 1-7nM.In other embodiments, method of the present invention comprises and gives vitamin D compounds, or the dosage of its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, can make the plasma concentration of vitamin D compounds reach about 3-7nM.In other embodiments, method of the present invention comprises and gives vitamin D compounds, or the dosage of its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, can make the plasma concentration of vitamin D compounds reach about 5-7nM.In other embodiments, method of the present invention comprises and gives vitamin D compounds, or the dosage of its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, can make the plasma concentration of vitamin D compounds reach about 3-5nM.
In certain embodiments, method of the present invention comprises and gives vitamin D compounds, or the dosage of its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, can make the plasma concentration of vitamin D compounds quick, for example in 4 hours, reach peak value.In other embodiments, method of the present invention comprises and gives vitamin D compounds, or the dosage of its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug, can make it quick, for example in less than 12 hours elimination half-life, eliminate.
In others, method of the present invention comprises that interruption gives the vitamin D compounds of MDS patient's high dose, and monitors this patient's hypercalcemia related symptoms.In certain embodiments, method of the present invention comprises that interruption gives the vitamin D compounds of MDS patient's high dose, and monitors this patients " renal function.In other embodiments, method of the present invention comprises that interruption gives the vitamin D compounds of MDS patient's high dose, and monitors this patient's soft tissue, for example the calcification situation of cardiac muscular tissue.In other embodiments, method of the present invention comprises that interruption gives the vitamin D compounds of MDS patient's high dose, and monitors this patient's bone density rising situation.In other embodiments, method of the present invention comprises that interruption gives the vitamin D compounds of MDS patient's high dose, and monitors the nephropathy situation of this patient's hypercalcemia.In other embodiments, method of the present invention comprises that interruption gives the vitamin D compounds of MDS patient's high dose, and monitors that this patient's blood calcium concentration is lower than about 10.5mg/dL to guarantee blood calcium concentration.
In certain embodiments, can obtain the blood high level of vitamin D compounds and following safely reduces calcium and shifts and enter blood.In one embodiment, obtained safely when administration and when following the diet that reduces calcium higher 1,25-dihydroxyvitamin D concentration and hypercalcemia does not take place.In one embodiment, can pass through adsorbent, absorbent, chelating agen or other binding molecule, with calcium catch make calcium can not by the transhipment enter blood by small intestinal.In another embodiment, can be by giving, for example (NovartisPharmaceutical Corp., East Hanover NJ) wait diphosphate and vitamin D compounds, suppress the osteoclast active rate for Sodium Pamidronate or ZOMETA.
In certain embodiments, can obtain the high-level clearance rate that also at utmost improves calcium of blood of vitamin D compounds safely.In one embodiment, can absorb the drainage that improves calcium by guaranteeing competent drinking-water and salt.In another embodiment, can utilize diuretic theraphy to improve the drainage of calcium.
Give vitamin D compounds and unite other medicine
Method of the present invention also provides therapeutic alliance, comprises that giving one or more vitamin D compounds unites other active medicine that one or more are not vitamin D compounds.Described other active medicine is unrestricted, can be any medicine that has treatment MDS or alleviate the therapeutic effect of its symptom well known by persons skilled in the art.These active medicines have been proposed its mechanism of action, can in this technical literature, find (for example see chief editors such as Hardman., 1996, Goodman; Gilman ' s The Pharmacological Basis of Therapeutics the 10th edition, McGraw-Hill, New York.643-754,1381-1484,1649-1678 page or leaf, and Physician ' s DeskReference (PDR) the 55th edition., 2001, Medical Economic Co., Inc., Montvale, NJ.In certain embodiments, therapeutic alliance of the present invention comprises giving one or more other active medicines, by producing superposition or synergism, improves the treatment or the remission effect of vitamin D compounds.
According to the present invention, this combinational therapeutic methods can be advantageously used in treatment MDS or alleviate basic symptom.The every wheel in the therapeutic scheme, giving one or more vitamin D compounds can be prior to (for example, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 5 days, 1 week, 2 weeks, January or longer), the back is in (for example, 0.5 hour, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 5 days, 1 week, 2 weeks, January or longer), give with one or more other active medicines simultaneously.Give other active medicine not as vitamin D compounds like that through often, preferably in the previous day that gives one or more other active medicines, give one or more vitamin D compounds.
In certain embodiments, other is not that the active medicine of vitamin D compounds can be one or more somatomedin.Described somatomedin can every take turns the inventive method give vitamin D compounds before, give simultaneously or afterwards, but to benefit the ability that somatomedin is reacted from vitamin D compounds sensitized cell.Like this, can adopt less somatomedin to treat MDS or alleviate its symptom.In other embodiments, adopt periodically treatment to suppress drug-fast generation or reduce Drug resistance, avoid or reduce the side effect of this treatment, and/or improve the effect of these treatments one or more treatments.
In certain embodiments, one or more somatomedin can be cytokines.Described cytokine can every take turns the inventive method give vitamin D compounds before, give simultaneously or afterwards.In other embodiments, one or more somatomedin can be hemopoietic growth factors.Described hemopoietic growth factor can every take turns the inventive method give vitamin D compounds before, give simultaneously or afterwards.
In certain embodiments, can every take turns the inventive method give vitamin D compounds before, simultaneously or the hemopoietic growth factor that gives afterwards can be: EPO, as r-HuEPO, or its pharmaceutical active mutant or derivant.In other embodiments, can every take turns the inventive method give vitamin D compounds before, simultaneously or the hemopoietic growth factor that gives afterwards can be G-CSF, as r-metHuG-CSF, or its pharmaceutical active mutant or derivant.In still other embodiment, can every take turns the inventive method give vitamin D compounds before, simultaneously or the hemopoietic growth factor that gives afterwards can be EPO and G-CSF, or their the pharmaceutical active mutant or the combination of derivant.In other embodiments, vitamin D compounds can be used as pre-concentration Emulsion and EPO, G-CSF combination, or with their pharmaceutical active mutant or derivant combination medicine-feeding.
In certain embodiments, give patient treatment MDS or alleviate the r-HuEPO of its symptom, or the dosage range of its pharmaceutical active mutant or derivant is about 1-2000 unit/kilogram, time (TIW) on every Wendesdays, preferred about 10-1000 unit/kilogram TIW, more preferably from about 25-500 unit/kilogram TIW.In other embodiments, the dosage that gives patient treatment MDS or alleviate the r-HuEPO of its symptom is about 1,10,20,50,100,200,300,400,500,750,1000,1250,1500,1750,2000 unit/kilograms, or dosage range wherein.In other embodiments, r-HuEPO can give with one or more vitamin D compounds, wherein, gives one or more vitamin D compounds according to dosage as herein described and scheme.
In certain embodiments, give patient treatment MDS or alleviate the r-metHuG-CSF of its symptom, or its pharmaceutical active mutant or derivative doses scope can be about 1-100 μ g/kg/ days, preferably about 3-75 μ g/kg/ days, more preferably from about 5-50 μ g/kg/ days.In other embodiments, the dosage that gives patient treatment MDS or alleviate the r-metHuG-CSF of its symptom is about 1,5,10,20,30,40,50,60,70,80,90,100 μ g/kg, or any dosage range wherein.In other embodiments, r-metHuG-CSF, or its pharmaceutical active mutant or derivant can give with one or more vitamin D compounds, wherein, gives one or more vitamin D compounds according to dosage as herein described and scheme.
In other embodiments, vitamin D compounds can with r-HuEPO, r-metHuG-CSF, or its pharmaceutical active mutant or derivant, or combining of they gives, wherein r-HuEPO, r-metHuG-CSF, or its pharmaceutical active mutant or derivant give by above-mentioned dosage respectively.
In certain embodiments, hemopoietic growth factor is r-HuEPO, every take turns give vitamin D compounds before, simultaneously or give afterwards, the dosage range that wherein gives r-HuEPO is about 50-100 unit/kilogram TIW.In other embodiments, hemopoietic growth factor is r-metHuG-CSF, every take turns give vitamin D compounds before, simultaneously or give afterwards, the dosage range that wherein gives r-metHuG-CSF is about 5-25 unit/kilogram TIW.In other embodiments, hemopoietic growth factor is the combination of r-HuEPO and r-metHuG-CSF, every take turns give vitamin D compounds before, simultaneously or give afterwards, the dosage range that wherein gives r-HuEPO is the about 25--500 unit of r-HuEPO/kilogram TIW, and r-metHuG-CSF is 5-25 μ g/kg/ days.
In other embodiments, every take turns give vitamin D compounds before, simultaneously or the somatomedin that gives afterwards be: IL-1, IL-2, IL-3, IL-4, IL-6, IL-8, IL-11, IL-12, IFN-α, GM-CSF, TPO, or its pharmaceutical active mutant or derivant.In other embodiments, every take turns give vitamin D compounds before, simultaneously or the somatomedin that gives afterwards be: IL-1, IL-2, IL-3, IL-4, IL-6, IL-8, IL-11, IL-12, IFN-α, GM-CSF, TPO, or its pharmaceutical active mutant or derivant.In other embodiments, vitamin D compounds can be used as pre-concentration Emulsion, with r-HuEPO, r-metHuG-CSF, IL-1, IL-2, IL-3, IL-4, IL-6, IL-8, IL-11, IL-12, IFN-α, GM-CSF, TPO, or one or more of its pharmaceutical active mutant or derivant, or combining of they gives.
In other embodiments, described is not that other active medicine of vitamin D compounds can be an immunomodulator.This immunomodulator can by the inventive method every take turns give vitamin D compounds before, simultaneously or give afterwards.In certain embodiments, this immunomodulator can be: ATG, ALG, thalidomide (thalidomide), prednisone, CyA, dexamethasone or pentoxifylline.In other embodiments, this immunomodulator can be: ATG, ALG, thalidomide, prednisone, CyA, dexamethasone or pentoxifylline.Also in other embodiments, vitamin D compounds can be used as pre-concentration Emulsion and ATG, ALG, thalidomide, prednisone, CyA, dexamethasone or pentoxifylline, or combining of they give.
In one specific embodiment, this immunomodulator is ATG, wherein the about 10-100mg/kg/ of dosage range days of giving of this ATG.In an embodiment preferred, this immunomodulator is ATG, wherein the about 35-45mg/kg/ of dosage range days of giving of this ATG.In another specific embodiment, this immunomodulator is a thalidomide, wherein the about 50-500mg/ of dosage range days of giving of this thalidomide.In an embodiment preferred, this immunomodulator is a thalidomide, wherein the about 100-400mg/ of dosage range days of giving of this thalidomide.
In other embodiments, described is not that other active medicine of vitamin D compounds can be the cytotoxicity preparation.This cytotoxicity preparation can by the inventive method every take turns give vitamin D compounds before, simultaneously or give afterwards.In certain embodiments, this cytotoxicity preparation can be: antimetabolite, anti-microtubule medicine, alkanisation preparation, cisplatin formulations, anthracyclines, antibiotics preparation or topoisomerase enzyme inhibitor; Also in other embodiments, vitamin D compounds can be used as one or more of pre-concentration Emulsion and antimetabolite, anti-microtubule medicine, alkanisation preparation, cisplatin formulations, anthracyclines, antibiotics preparation or topoisomerase enzyme inhibitor, or combining of they gives.
In other embodiments, the cytotoxicity preparation can be: one of cytosine arabinoside, melphalan, topotecan, fludarabine, etoposide, O-Demethyldaunomycin, daunorubicin, mitoxantrone, cisplatin, paclitaxel and cyclophosphamide.In other embodiments, the cytotoxicity preparation can be more than one cytosine arabinoside, melphalan, topotecan, fludarabine, etoposide, O-Demethyldaunomycin, daunorubicin, mitoxantrone, cisplatin, paclitaxel and cyclophosphamide.Also in other embodiments, vitamin D compounds can be used as one or more of pre-concentration Emulsion and cytosine arabinoside, melphalan, topotecan, fludarabine, etoposide, O-Demethyldaunomycin, daunorubicin, mitoxantrone, cisplatin, paclitaxel and cyclophosphamide, or combining of they gives.
In one specific embodiment, described cytotoxicity preparation is a cytosine arabinoside, and wherein the dosage scope of cytosine arabinoside is about 10mg-1g/m 2/ day.In an embodiment preferred, described cytotoxicity preparation is a cytosine arabinoside, and wherein the dosage scope of cytosine arabinoside is about 5mg-20mg/m 2/ day.In another specific embodiment, the cytotoxicity preparation is an O-Demethyldaunomycin, and wherein the dosage scope of O-Demethyldaunomycin is about 9-18mg/m 2/ day.In another specific embodiment, the cytotoxicity preparation is a melphalan, and wherein the dosage scope of melphalan is 1-100mg/ days.In an embodiment preferred, the cytotoxicity preparation is a melphalan, and wherein the dosage scope of melphalan is about 1-5mg/ days.In another specific embodiment, the cytotoxicity preparation is a topotecan, and wherein the dosage scope of topotecan is about 1-100mg/m 2/ day.In an embodiment preferred, the cytotoxicity preparation is a topotecan, and wherein the dosage scope of topotecan is about 1-5mg/m 2/ day.
In other embodiments, described is not that other active medicine of vitamin D compounds can be one or more medicines that can influence rna transcription.The described medicine that can influence rna transcription can by the inventive method every take turns give vitamin D compounds before, simultaneously or give afterwards.In certain embodiments, the medicine that can influence rna transcription can be one of decitabing, 5-azacytidine, depside peptide (depsipeptides) and phenyl butyrate.In other embodiments, the medicine that can influence rna transcription can be more than one decitabing, 5-azacytidine, depside peptide and phenyl butyrate.Still in other embodiments, vitamin D compounds can be used as one or more of pre-concentration Emulsion and decitabing, 5-azacytidine or depside peptide, or combining of they gives.
In one specific embodiment, the medicine that can influence rna transcription is a decitabing, and wherein the dosage scope of decitabing is about 10-200mg/m 2/ day.In an embodiment preferred, the medicine that can influence rna transcription is a decitabing, and wherein the dosage scope of decitabing is about 45-100mg/m 2/ day.In another specific embodiment, the medicine that can influence rna transcription is a 5-azacytidine, and wherein the dosage scope of 5-azacytidine is about 5-200mg/m 2/ day.In an embodiment preferred, the medicine that can influence rna transcription is a 5-azacytidine, and wherein the dosage scope of 5-azacytidine is about 10-75mg/m 2/ day.
In other embodiments, described is not that other active medicine of vitamin D compounds can be the derivant of vitamin A, E or K.The derivant of vitamin A, E or K can by the inventive method every take turns give vitamin D compounds before, simultaneously or give afterwards.In certain embodiments, suitable-tretinoin that the derivant of vitamin A, E or K can be trans retinoic acid (ATRA), 13-, tocopherol and Menaquinone K6.In other embodiments, suitable-tretinoin that vitamin D compounds can be used as pre-concentration Emulsion and trans retinoic acid, 13-, tocopherol and vitamin K 2One or more, or they combine administration.
In one specific embodiment, the derivant of vitamin A, E or K is ATRA, and wherein the dosage scope of ATRA is about 10-200mg/m 2/ day.In an embodiment preferred, the derivant of vitamin A, E or K is ATRA, and wherein the dosage scope of ATRA is about 25-80mg/m 2/ day.In another embodiment preferred, the derivant of vitamin A, E or K be 13-suitable-tretinoin, wherein 13-suitable-the dosage scope of tretinoin is about 5-200mg/m 2/ day.In an embodiment preferred, the derivant of vitamin A, E or K be 13-suitable-tretinoin, wherein 13-suitable-the dosage scope of tretinoin is about 10-100mg/m 2/ day.In another specific embodiment, the derivant of vitamin A, E or K is a Menaquinone K6, and wherein the dosage scope of Menaquinone K6 is about 5-200mg/m 2/ day.In an embodiment preferred, the derivant of vitamin A, E or K is a Menaquinone K6, and wherein the dosage scope of Menaquinone K6 is 10-100mg/ days.In another embodiment preferred, the derivant of vitamin A, E or K is a tocopherol, and wherein the dosage scope of tocopherol is about 400-3000IU/ days.In an embodiment preferred, the derivant of vitamin A, E or K is a tocopherol, and wherein the dosage scope of tocopherol is about 800-2000IU/ days.
In other embodiments, described be not other active medicine of vitamin D compounds can be can specificity in conjunction with the medicine of MDS associated biomolecule target.Can specificity in conjunction with the medicine of MDS associated biomolecule target, can by the inventive method every take turns give vitamin D compounds before, simultaneously or give afterwards.In certain embodiments, the energy specificity can be anti-VEGF, gemtuzumabozogamicin and TNFR:Fc in conjunction with the medicine of MDS associated biomolecule target.In other embodiments, vitamin D compounds can be used as one or more of pre-concentration Emulsion and anti-VEGF, gemtuzumab ozogamicin and TNFR:Fc, or they combine administration.In other embodiments, vitamin D compounds can be used as one or more of pre-concentration Emulsion and anti-VEGF, gemtuzumab ozogamicin and TNFR:Fc, or they combine administration.In one specific embodiment, the energy specificity is gemtuzumabozogamicin in conjunction with the medicine of MDS associated biomolecule target, and wherein the dosage scope of gemtuzumab ozogamicin is about 5-20mg/m 2/ week.
In other embodiments, described is not that other active medicine of vitamin D compounds can be a signal transduction inhibitor.Signal transduction inhibitor can by the inventive method every take turns give vitamin D compounds before, simultaneously or give afterwards.In certain embodiments, signal transduction inhibitor can be one or more methods Buddhist nun inhibitors.In other embodiments, this method Buddhist nun inhibitors can be Zarnestra TMAnd Sarasar TMOne of.In other embodiments, this method Buddhist nun inhibitors can be more than one Zarnestra TMAnd Sarasar TMIn other embodiments, vitamin D compounds can be used as pre-concentration Emulsion and one or more Zarnestra TMAnd Sarasar TMOr they combine administration.
In other embodiments, signal transduction inhibitor can be a tyrosine kinase inhibitor.This tyrosine kinase inhibitor can by the inventive method every take turns give vitamin D compounds before, simultaneously or give afterwards.In certain embodiments, this tyrosine kinase inhibitor can be one of SU5416, SU6668 or PTK787/ZK222584.In certain embodiments, this tyrosine kinase inhibitor can be one or more of SU5416, SU6668, PTK787/ZK222584, or their combination.
In other embodiments, described is not that other active medicine of vitamin D compounds can be an amineothiot.This amineothiot can by the inventive method every take turns give vitamin D compounds before, simultaneously or give afterwards.In one specific embodiment, this amineothiot is an Amifostine.In another specific embodiment, vitamin D compounds can be used as pre-concentration Emulsion with the Amifostine administration.In another specific embodiment, amineothiot is Amifostine (amifostine), wherein the dosage scope of Amifostine when administration in the time of many days for about 50-600mg/m 2/ day, maybe when giving single agent 600mg-1.2g/m 2In an embodiment preferred, amineothiot is an Amifostine, and when administration in the time of many days, the dosage scope of Amifostine is about 100-400mg/m 2/ day, when giving single agent about 740-910mg/m 2
In other embodiments, described is not that other active medicine of vitamin D compounds can be an arsenical.This arsenical can by the inventive method every take turns give vitamin D compounds before, simultaneously or give afterwards.In one specific embodiment, this arsenical is an arsenic trioxide.In another specific embodiment, vitamin D compounds can be used as pre-concentration Emulsion with the arsenic trioxide administration.
The dosage of above-mentioned any combination medicine-feeding, administration number of times and persistent period also may be different with route of administration, pharmacokinetics and the pharmacodynamic action of previously medical history and pharmaceutical preparation because of patient's age, body weight, reaction.These factors are that this those skilled in the art's routine will be considered.Other dosage that these those skilled in the art will consider when the design dosage more than had been discussed and the example of factor.
Medication
In the method for the invention, available any method afford vitamin D compounds well known by persons skilled in the art.In certain embodiments, the known any conventional method that the vitamin D compounds plasma concentration is peaked rapidly of available art technology person gives vitamin D compounds.In other embodiments, vitamin D compounds oral administration, mucosa or parenteral.For example the mucosal administration vitamin D compounds comprises nasal cavity, Sublingual, vagina, mouthful cheek or rectally, and the parenteral administration vitamin D compounds comprises intravenous, intramuscular or intra-arterial administration.Vitamin D compounds can medicine group be injected when intravenous or intra-arterial administration, or the perfusion administration of a few minutes to a few hours.In preferred embodiments, vitamin D compounds can oral or intravenous administration.
The administration time of vitamin D compounds also can be different.No matter the vitamin D compounds dosage form is how, can be in every the wheel before one or more other active medicines as Synergistic treatment, give simultaneously or afterwards.Also can give vitamin D compounds and preparation in the therapeutic scheme, for example between a series of circulations of these other treatments or simultaneously, give vitamin D compounds and other medicine every the wheel.In certain embodiments, vitamin D compounds can be according to seriality or the scheme discontinuity administration of noncontinuity time.
In addition, the inventive method also comprises and gives one or more other active medicines, and this other active medicine can be with any method administration that those skilled in the art will know that.
The pharmaceutical preparation of vitamin D compounds
In order to be used for the present invention, this pharmaceutical preparation can contain one or more vitamin D compounds, or one or more the optional vitamin D compounds and the combination of one or more other active medicines.In treatment during MDS, this pharmaceutical preparation also can with one or more other active medicines, give together as hemopoietic growth factor or cytokine.This pharmaceutical preparation can be any pharmaceutical dosage form well known by persons skilled in the art.Common pharmaceutical preparation of the present invention and dosage form contain at least a vitamin D compounds, or its pharmaceutically acceptable salt, solvate, hydrate, stereoisomer, clathrate or prodrug.Pharmaceutical preparation of the present invention also can comprise relevant any other component of one or more excipient, diluent or compound method well known by persons skilled in the art and of the present invention with dosage form.Pharmaceutical preparation of the present invention and dosage form also can comprise other active component that is not vitamin D compounds.In addition, can utilize pharmaceutical preparation of the present invention to prepare unit dosage forms.
Compositions, shape and dosage form usually according to they purposes and different.For example, be used for the dosage form of acute treatment disease, compare, can contain relatively large pharmaceutical preparation with the dosage form that is used for a kind of disease chronic treatment.Similarly, parenteral dosage form is compared with the peroral dosage form that is used for the treatment of with a kind of disease, can contain more a spot of pharmaceutical preparation.In these and other method, those skilled in the art are not difficult to understand that concrete dosage form can be different.For example see Remington ' s Pharmaceutical Sciences, the 18th edition, Mack Publisfhing, EastonPA (1990).
That dosage form should be fit to is oral, mucosa such as nasal cavity, Sublingual, vagina, mouthful cheek or rectally, or gastrointestinal tract is outer as intravenous, intramuscular or intra-arterial administration.When vitamin D compounds during through intravenous or intra-arterial administration, can the injection of medicine group, or the perfusion of a few minutes to a few hours gives vitamin D compounds.The example of dosage form includes but not limited to: tablet, capsule sheet, capsule such as hard and Perle, cachet, lozenge, lozenge, dispersion liquid, suppository, ointment, paste (plaster), paste, medicated powder, dressing, medicine frost, serosity, solution, paster, aerosol such as nasal spray or inhalant and gel.Being fit to dosage form oral or mucosa delivery includes but not limited to: aqueous or non-aqueous liquid suspension, oil in water emulsion, water in oil emulsion, solution and elixir.Liquid dosage form includes but not limited to it can is that crystal or unbodied sterilization solid are redeveloped into the liquid dosage form that is fit to the gastrointestinal tract external administration.
The preferred dosage form of the present invention comprises peroral dosage form and intravenous form.When discontinuity orally give vitamin D compounds, should give vitamin D compounds with pre-concentration Emulsion form.In the preference embodiment of vitamin D compounds peroral dosage form, this peroral dosage form is the vitamin D compounds pre-concentration Emulsion that contains about 15 microgram calcitriols and following quantity excipient, and described excipient and about percentage by weight thereof are: 65%Miglyol
Figure C20038010737900421
30%Gelucire
Figure C20038010737900422
5% vitamin E TPGS and Yoshinox BHT (BHT) and butylated hydroxyanisol (BHA) each about 0.05%.In the optimum option embodiment of intravenous form vitamin D compounds, this intravenous dosage forms is
Figure C20038010737900423
It contains 1 μ g calcitriol, 4mg Polysorbate20,2.5mg sodium ascorbate and optional pH regulator agent HCl or NaOH.
Typical pharmaceutical preparation and dosage form comprise one or more excipient.Suitable excipient is well known to those skilled in the art, and its non-limitative example is provided by this paper.Whether concrete excipient is fit to mix depends on various factors well known in the art in pharmaceutical preparation or the dosage form, include but not limited to the route of administration of this dosage form.In one embodiment, peroral dosage form is tablet for example, can contain the excipient that is not suitable for the outer dosage form of gastrointestinal tract.The suitability of concrete excipient also can be depending on the concrete medicine in this dosage form.
In certain embodiments, this pharmaceutical preparation and dosage form can be anhydrous, because water and heating may promote the degraded of some chemical compound.Therefore, water and heat may be clearly to the effect of preparation, because preparation normal dampness and/or moisture content of meeting with in manufacturing, processing, packing, storage, transportation and use.
Can adopt anhydrous or contain the composition of low moisture content and anhydrous pharmaceutical preparation of preparation and dosage form under low humidity or low moisture content condition.In preferred embodiments, anhydrous pharmaceutical preparation is made, stores and packed to the material that employing can prevent to contact water and help producing suitable prescription medicine box to save water-less environment from damage.Suitable examples of material includes but not limited to: hermetic seal metal platinum, plastics and unit dose container, and as bottle, foam filled packing and bar shaped packing.
In certain embodiments, this pharmaceutical preparation and dosage form contain one or more stabilizing agents, and stabilizing agent is the chemical compound that can reduce the active component decomposition rate, includes but not limited to: antioxidant such as ascorbic acid, pH buffer agent or salt buffer agent.
Pharmaceutical preparation of the present invention can be, for example semi-solid preparation or liquid preparation.Semi-solid preparation of the present invention can be the known any semi-solid preparations of those of ordinary skills, for example comprises: gel, cream paste, frost and ointment.
In certain embodiments, this pharmaceutical preparation can contain the vitamin D compounds goods of present clinical use.The example of this biostearin D chemical compound goods and congener includes but not limited to: dihydrotachysterol (DHT TM, Roxane; With
Figure C20038010737900424
Sanofi Winthrop Pharm); Calcitriol (
Figure C20038010737900425
Roche and
Figure C20038010737900431
Abbott); The calcification glycol (
Figure C20038010737900432
Organon); Ostelin (
Figure C20038010737900433
Schwarz Pharma;
Figure C20038010737900434
Sanofi Pharm); Ostelin ( Vitamin D3, Freeda); Secondary calcitriol (
Figure C20038010737900436
Abbott); 1-α HEC (
Figure C20038010737900437
Bone Care Int ' 1); And α-calcitriol (
Figure C20038010737900438
Figure C20038010737900439
)
Figure C200380107379004310
Be a kind of calcitriol preparation of present clinical practice, available capsule contains the calcitriol of 0.25 μ g and 0.5 μ g, and oral liquid contains 1 μ g/ml calcitriol.
Figure C200380107379004311
Dosage form can contain other component, as Yoshinox BHT (BHT) and butylated hydroxyanisol (BHA) as antioxidant.Capsule also can contain the triglyceride that the Oleum Cocois fractional distillation is arrived, and oral liquid contains the triglyceride that palmit seed oil is fractionated to.See Physicians ' Desk Reference 2991 (the 56th edition, 2002).
Peroral dosage form
In certain embodiments, but this pharmaceutical preparation of orally give.The secretion dosage form of the pharmaceutical preparation that is fit to oral administration can be provided, include but not limited to: tablet and chewable tablet, capsule sheet, capsule and liquid such as seasoning syrup.This dosage form contains the pharmaceutical preparation of the amount of pre-determining, the pharmaceutical methods preparation that available these those skilled in the art know.See Remington ' sPharmaceutical Sciences, 18 editions, Mack Publishing, Easton PA (1990).
Pharmaceutical technology according to routine prepares typical peroral dosage form with pharmaceutical preparation and at least a mixed with excipients.The desirable wide range of forms of excipient.For example, the excipient that is suitable as oral liquid or aerosol dosage forms includes but not limited to: water, ethylene glycol, oil, alcohol, flavoring agent, antiseptic and coloring agent.The excipient example that is suitable as oral dosage form such as medicated powder, tablet, capsule and capsule sheet includes but not limited to: starch, sugar, microcrystalline Cellulose, diluent, granulation agent, lubricant, binding agent and disintegrating agent.
In certain embodiments, the binding agent of adequate types includes but not limited to: corn starch, potato starch, other starch, gelatin, natural or synthetic natural gum such as arabic gum, sodium alginate, alginic acid, other alginate, powdery Huang are had a liking for glue, guar gum, cellulose and derivant thereof.The example of cellulose derivative includes but not limited to: ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose.Other binding agent includes but not limited to: polyvinylpyrrolidone, methylcellulose, pregelatinized Starch, hydroxypropyl emthylcellulose, microcrystalline Cellulose and their mixture.
The microcrystalline Cellulose of adequate types includes but not limited to: those commodity are called
Figure C200380107379004312
Figure C200380107379004313
Figure C200380107379004314
AVICEL
Figure C200380107379004315
Figure C200380107379004316
(
Figure C200380107379004317
Product is available from FMC Corporation, American Viscose Division, and AvicelSales, Marcus Hook, PA) and their mixture.In certain embodiments, binding agent can be the mixture of microcrystalline Cellulose and sodium carboxymethyl cellulose, sells to be Avicel Suitable anhydrous or low moisture content excipient or additive comprise:
Figure C20038010737900441
With ATARCH 1500
Figure C20038010737900442
In certain embodiments, suitable filler includes but not limited to: Talcum, calcium carbonate, microcrystalline Cellulose, Powderd cellulose, glucosan, potter's clay, mannitol, silicic acid, sorbitol, starch, pregelatinized Starch and their mixture.The percentage by weight that binding agent or filler exist accounts for about 50-99% of pharmaceutical preparation or dosage form
In certain embodiments, can in preparation, adopt disintegrating agent so that disintegrate during tablet contact water environment.The tablet that contains too many disintegrating agent can disintegrate when storing, but content can not or disintegrate take place at desired conditions with required speed very little the time.Therefore should adopt the both not many also not disintegrating agent very little of q.s to prepare peroral dosage form, the release of conclusive change pharmaceutical preparation.The consumption of disintegrate dosage is different according to the type of preparation, and these those skilled in the art are not difficult to determine.In certain embodiments, the disintegrating agent that contains of this pharmaceutical preparation accounts for about 0.5-15% of weight.In a preferred embodiment, this pharmaceutical preparation contains the disintegrating agent of about 1-5% weight.
In other embodiments, suitable disintegrants includes but not limited to: the Carboxymethyl cellulose sodium of agar, alginic acid, calcium carbonate, microcrystalline Cellulose, interlinkage, crospovidone, polacrilin potassium, starch mannitic acid sodium, Rhizoma Solani tuber osi or tapioca, other starch, pregelatinized Starch, other starch, potter's clay, other ammonium alginate, other cellulose, natural gum and their mixture.
In certain embodiments, examples of suitable lubricants includes but not limited to: the hydride of sodium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, Polyethylene Glycol, other glycol, stearic acid, sodium lauryl sulfate, Talcum and vegetable oil such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, Oleum helianthi, Oleum sesami, Fructus Canarii albi Brassica campestris L, Semen Maydis oil and Oleum Glycines.In other embodiments, examples of suitable lubricants includes but not limited to: zinc stearate, ethyl oleate, ethyl laurate, agar and their mixture.In other embodiments, examples of suitable lubricants includes but not limited to: syloid silica gel such as Aerosil 200 (W.R.Grace Co.of Baltimore, MD makes), a kind of cohesion aerosol of synthetic silica (by Degussa Co.of Plano, TX sells) and their mixture.When adopting lubricant, their general amounts that exists are no more than 1% weight of pharmaceutical preparation or dosage form.
In certain embodiments, peroral dosage form can be tablet and capsule.Tablet and capsule can contain solid excipient, owing to be easy to carry the oral single dosage form that can provide the best.As needs, the aqueous of tablet available standards or non-aqueous technology coatings.Usually, by all even close hybrid medicine preparation and liquid-carrier, finely-divided solid carrier or the two make product form required shape then and come useful in preparing drug formulations and dosage form.For example, can suppress or die casting prepares tablet.Prepare slugging by compacting medicine in suitable machine and optional excipient.Equally can be in suitable machine, die casting prepares the die casting tablet with medicine and the optional excipient that the inert diluent body drenches.
In certain embodiments, the unit dosage forms of said composition is a capsule, and interior middle composition total capacity is preferably about 10-1000 μ L.In preferred embodiments, the about 100-300 μ of the total capacity L of composition in the capsule.
The relative scale of each composition is looked the physical features of the concrete function of particular type, each composition of compositions, concrete composition and required product and different in the said preparation.For example, certain component may be local free-pouring liquid or the serosity that uses.Determine that the work ratio under any concrete condition belongs within the limit of power of this field those of ordinary skill.Following all ratios that mark and relative weight are represented preferred technology, but not limit by any way.
Calcitriol may be to photaesthesia oxidation especially easily.And calcitriol and other active vitamin D compounds be lipotropy, means that they dissolve in lipid and some organic solution, but be insoluble in polarizable medium such as water.Because the lipotropy of active vitamin D compounds will be dispersed in aqueous solution with this compounds, and is in gastric juice, obviously very limited.Therefore, the pharmacokinetic parameter of present available active vitamin D compounds preparation is inferior suitable property.As a result, present available active vitamin D compounds preparation tends to show absorbance great changes have taken place property in small intestinal.
Yet, in some preferred embodiment of the present invention, improve its stability under elevated temperature even vitamin D compounds can be mixed with pre-concentration Emulsion, improve pharmacokinetic parameter and reduce the variability that in small intestinal, absorbs.Preferably, the active vitamin D compounds that this method provides has sufficiently high concentration and convenient the use as the dosage form of calcitriol.This dosage form all is tablet under different temperatures, can include but not limited to form nano dispersion fluid in the gastric juice rapidly at polarizable medium, plays a role with required pharmacokinetic parameter simultaneously.
During high dose, the highest blood concentration of vitamin D compounds that this pre-concentration Emulsion shows is at least than employing
Figure C20038010737900451
The seen high 1.5-2 of the highest blood concentration doubly.Half-life is to adopt
Figure C20038010737900452
Seen half or less than half, the time ratio that reaches maximum plasma concentration adopts
Figure C20038010737900453
The seen time is short.In these years pharmacokinetic characteristic helps vitamin D compounds and reaches blood high level and hypercalcemia does not take place, and clinical hypercalcemia does not preferably take place.
In certain embodiments, this pre-concentration Emulsion when promptly polarizable medium includes but not limited to the water dilution, can form emulsion with liquid or solution isopolarity component.The ratio of polarizable medium and pre-concentration Emulsion is preferably 1: 1 or is higher.In one embodiment, the ratio of water and compositions can be about 1: 1-5000: 1.In another embodiment, the ratio of water and compositions can be about 1: 1,2: 1,3: 1,4: 1,5: 1,10: 1,200: 1,300: 1,500: 1,1000: 1 or 5000: 1, or any ratio in this scope.Proper proportion when those skilled in the art can determine required the application.
In other embodiments, this emulsion can be the submicron droplets emulsion, wherein, this submicron droplets emulsion has one or more following features: (1) is not though there is the energy can both spontaneously form emulsion as heating, high shear stirring or other substantive stirring when all compositions are contacted, (2) thermokinetics stable performance, (3) are homogeneous state.
Drop in the submicron droplets emulsion or granule can have different shape, include but not limited to: spherical, as to be with cell liquid crystal, hexahedron or isotropism antitrope.The average diameter scope that contained drop of submicron droplets emulsion or granule have is generally about 50-1000nm, preferably about 100-750nm, more preferably from about 200-400nm.
In certain embodiments, when with polarizable medium such as water dilution pre-concentration Emulsion, the 400nm light absorption value of gained emulsion is about 0.3-15.0.In other embodiments, the 400nm light absorption value of gained emulsion is about 0.3-8.0.In certain embodiments, this light absorption value is about 0.4,0.5,0.6,1.0,1.2,1.6,2.0,2.2,2.4,2.5,3.0 or 4.0 when 400nm, or any light absorption value in this scope.In preferred embodiments, the emulsion 400nm light absorption value scope of water and pre-concentration Emulsion dilution formation in 100: 1 is about 0.3-4.0.The method of measuring the solution light absorption value is well known to those skilled in the art.Those skilled in the art can determine and adjust the relative scale of all compositions of pre-concentration Emulsion of the present invention, to obtain its specific light absorption value emulsion within the scope of the present invention with polarizable medium such as water dilution the time.
In certain embodiments, this pre-concentration Emulsion contains (a) one or more lipophilic phase constituents, (b) one or more surfactants and (c) one or more vitamin D compounds; Wherein said compositions is a pre-concentration Emulsion, and it is with polarizable medium such as water, for example with water: about 1: 1 of compositions ratio or more during highly diluted, the emulsion of formation at the light absorption value of 400nm greater than 0.3.In certain embodiments, this pre-concentration Emulsion also can contain one or more hydrophobicitys or aqueous favoring composition.Vitamin D compounds in this pre-concentration Emulsion as mentioned above.Vitamin D compounds can be an active vitamin D compounds, or can be transformed into the chemical compound of active vitamin D compounds during administration.
The lipophilic phase constituent can be not with water-soluble mixed any pharmaceutically acceptable solvent.Typical lipophilic phase constituent comprises monoglyceride, diglyceride or triglyceride, includes but not limited to derived from C 6, C 8, C 10, C 12, C 14, C 16, C 18, C 20, and C 22Those esters of fatty acid.Exemplary diglyceride specifically comprises: diolein, two palm acid esters and blended capric acid-Sunfat GDC-S.Preferred triglyceride includes but not limited to: the triglyceride of vegetable oil, fish oil, Animal fat, hydrogenated vegetable oil, partially hydrogenated vegetable oil, the triglyceride of the triglyceride of synthetic triglyceride, modification, fractionated triglyceride, middle long chain triglyceride, structure and their mixture.
Preferred triglyceride includes but not limited to: almond oil, babassu oil, borage oil, postfermented tea bamboo comb oil, low erucic acid rapeseed oil, Oleum Ricini, Oleum Cocois, Semen Maydis oil, Oleum Gossypii semen, Radix Oenotherae erythrosepalae oil, Oleum Vitis viniferae, Oleum Arachidis hypogaeae semen, mustard seed oil, olive oil, Petiolus Trachycarpi oil, palmit seed oil, Oleum Arachidis hypogaeae semen, Oleum Vitis viniferae, safflower oil, Oleum sesami, shark liver oil, Oleum Glycines, sunflower oil, castor oil hydrogenated, hydrogenated coconut oil, hydrogenated palm oil, hydrogenated soybean oil, hydrogenated vegetable oil, hydrogenation Semen Gossypii and Oleum Ricini, partially hydrogenated Oleum Glycines, the triglyceride of partially hydrogenated Oleum Glycines and Oleum Gossypii semen, tricaproin, tricaprylin, tricaprin, glycerol hentriaconta-acid esters, trilaurin, triolein, linolein, trilinolenin, glycerol three caproic acids/decanoin, glycerol three caproic acids/capric acid/laurate, glycerol three caproic acids/capric acid/linoleate, with glycerol three caproic acids/capric acid/stearate.
In certain embodiments, the triglyceride of preference can be that commercialization is called Labrafac
Figure C20038010737900471
Medium chain triglyceride.Other preferred triglyceride comprises, for example, neutral oil such as indeterminate plant oil, can buy as commodity through the Oleum Cocois of fraction specifically
Figure C20038010737900472
Triglyceride, include but not limited to:
Figure C20038010737900473
Figure C20038010737900474
Figure C20038010737900475
With
Figure C20038010737900476
Preferred lipophilic phase constituent can be a product
Figure C20038010737900477
See United States Patent (USP) 5,342,625.
Other triglyceride that is fit to includes but not limited to: sad-tricaprin, be called as commercialization
Figure C20038010737900478
, include but not limited to: Other this series products that is fit to includes but not limited to:
Figure C200380107379004710
Figure C200380107379004711
Figure C200380107379004712
Figure C200380107379004714
And MAZOL
Figure C200380107379004715
As mentioned above, this pre-concentration Emulsion also comprises one or more surfactants.Adoptable surfactant comprises but is not limited to hydrophilic and lipophilic surfactant, includes but not limited to: anion, cation, nonionic and amphoteric surfactant or their mixture.In preferred embodiments, surfactant is non-ionic hydrophilic and nonionic lipophilic surfactant.
In certain embodiments, suitable hydrophilic surfactant active includes but not limited to the natural or hydrogenant vegetable oil of natural or hydrogenant vegetable oil and ethylene glycol such as Pegylation or the product of Oleum Ricini.Can include but not limited to make natural or hydrogenant Oleum Ricini and reacting ethylene oxide (its mol ratio about 1: 35-1: 60) obtain this product by known method.Choose wantonly, available German Auslegeschrifien 1,182,388 and 1,518, the method described in 819 is removed the free Polyethylene Glycol in the product.
Other lipophilic surfactant who is fit to includes but not limited to the pears alcohol-fatty acid ester of polyoxyethylene-dehydration, and it includes but not limited to: single and trilaurin, cetylate, stearate and oleate are called as following commercialization
Figure C200380107379004716
Product:
Figure C200380107379004717
(polyoxyethylene (20) Arlacel-20)
Figure C200380107379004718
(polyoxyethylene (20) Arlacel-40)
Figure C200380107379004719
(polyoxyethylene (20) Arlacel-60)
Figure C200380107379004720
(polyoxyethylene (20) Arlacel-80)
Figure C200380107379004721
(polyoxyethylene (20) Arlacel-65)
Figure C200380107379004722
(polyoxyethylene (20) sorbitan trioleate)
Figure C20038010737900481
(polyoxyethylene (4) sorbitan monolaurate)
Figure C20038010737900482
(polyoxyethylene (4) sorbitan monostearate)
Figure C20038010737900483
(polyoxyethylene (5) sorbitan monoleate)
This series products that is used for compositions of optimum option is TWEEN
Figure C20038010737900484
And TWEEN
Figure C20038010737900485
See the United States Patent (USP) 5,342,625 of Hauer etc.
In other embodiments, suitable hydrophilic surfactant active includes but not limited to: polyoxyethylene alkyl ether, polyoxyethylene glycol fatty acid ester such as Myrj 45, polyglycereol ester fat acid ester, polyoxyethylene glyceride, polyoxyethylene vegetable oil and polyethylene glycol hydrogenated vegetable oil.Other suitable hydrophilic surfactant active includes but not limited to the mix products of the one or more member's reactions in polyol and fatty acid, glyceride, vegetable oil, hydrogenated vegetable oil and the sterol; Polyoxyethylene-polyoxypropylene copolymer; And block copolymer; Dioctyl succinate, dioctyl sodium sulfosuccinate, two-[2-ethylhexyl]-succinate or sodium lauryl sulfate; Phospholipid preferably lecithin such as fabaceous lecithin; Propylene glycol list and double acid ester such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol hydroxy stearic acid ester, propylene glycol isostearate, propylene glycol laurate, propylene glycol monoricinolein and propylene glycol stearate.Most preferred fatty acid ester can be propylene glycol sad-the capric acid diester.Other suitable hydrophilic surfactant active includes but not limited to cholate such as sodium taurocholate.
In certain embodiments, suitable lipophilic surfactant includes but not limited to: alcohol, polyoxyethylene alkyl ether, fatty acid, bile acid glycerol ester fat acid ester, the acetoglyceride ester fat acid ester, the fatty acid low-carbon-ester, cithrol, the polyglycols fatty acid glyceride, the polypropylene glycol fatty acid ester, polyoxyethylene glyceride, list or diglycerol lactate, propylene glycol two glyceride, fatty acid esters of sorbitan, polyoxyethylene sorbitan fatty acid ester, polyox-yethylene-polyoxypropylene block copolymer, the vegetable oil of ester exchange, sterol, sugar ester, sugar ether, sucrose glyceride, the polyoxyethylene vegetable oil, polyethylene glycol hydrogenated vegetable oil.In other embodiments, suitable lipophilic surfactant includes but not limited to the mix products of the one or more member's reactions in polyhydric alcohol and fatty acid, glyceride, vegetable oil, hydrogenated vegetable oil and the sterol.
In other embodiments, suitable lipophilic surfactant includes but not limited to the ester exchange offspring of crude vegetal triglyceride and the many alcohol of polyalkylene.This ester exchange offspring is that this field is known, available United States Patent (USP) 3,288, and method described in 824 obtains.These ester exchange offsprings include but not limited to the reactant mixture of one or more crude vegetals such as Semen Maydis oil, nucleolus oil, almond oil, Oleum Arachidis hypogaeae semen, olive oil, Petiolus Trachycarpi oil and one or more Polyethylene Glycol.Preferred Polyethylene Glycol mean molecule quantity is 200-800.In a preferred embodiment, carry out the fat exchange by crude vegetal triglyceride and 2: 1 mol ratios of Polyethylene Glycol and obtain this kind product.Various forms of ester exchange offspring commodity are called
In certain embodiments, suitable lipophilic surfactant includes but not limited to fat soluble vitamin derivant such as tocopherol PEG-1000 succinate (" vitamin E TPGS "), monoglyceride, double glyceride and their mixture; The esterification products of sad or capric acid and glycerol; Fatty acid esters of sorbitan; Tetramethylolmethane and pentaerythritol fatty ester; With polyalkylene glycol such as Ji Wusi ester-dioleate ,-distearate ,-mono laurate is cruel ,-polyglycol ether; Cruel and the glyceryl monostearate of monoglyceride such as glycerin mono-fatty acid ester, glycerol list Palmic acid; Triacetin or (1,2,3)-glyceryl triacetate; Sterol and derivant include but not limited to cholesterol and derivant thereof, and specifically, plant sterol is as containing the product of sitosterol, campesterol or stigmasterol; With oxirane additive compound such as stigmasterol and derivant thereof.
Those of ordinary skills know that several commercial surface activator compositions contain little triglyceride to moderate.Therefore, in certain embodiments, be applicable to that the surfactant of pharmaceutical preparation of the present invention can comprise the surfactant that contains triglyceride.The example of commercial surface activator composition includes but not limited to
Figure C20038010737900491
Figure C20038010737900492
With The object lesson of these chemical compounds is the glyceride of saturated Pegylation, as GELUCIRE
Figure C20038010737900494
GELUCIRE GELUCIRE Semisynthetic triglyceride such as GELUCIRE
Figure C20038010737900497
GELUCIRE
Figure C20038010737900498
And other Surface activator composition is as 37/06,43/01,35/10,37/02,46/07,48/09,50/02,62/05 etc.
In other embodiments, suitable commercialization surface activator composition includes but not limited to glyceryl linoleate such as MAISINE
Figure C200380107379004910
With caprylic/capric glyceride such as IMWITOR
Figure C200380107379004911
See United States Patent (USP) 6,267,985.These those skilled in the art know other commercial surface activator composition that contains remarkable triglyceride composition in addition, understand that also the compositions that contains triglyceride and surfactant may be fit to provide the lipophilic phase component of all or part, and the surfactant of all or part.
In certain embodiments, pre-concentration Emulsion of the present invention can be chosen wantonly and contain the combined thing of one or more lipophilics.The combined thing of suitable lipophilic includes but not limited to alkanediol, preferred diether.One or more lipophilic phase component can contain, for example pharmaceutically acceptable C 1-C 5The tetrahydrofurfuryl ether of alkyl or low-molecular-weight list or poly--oxygen alkanediol.Alkanediol can be C 2-C 12Oxygen-alkanediol, preferred C 4-oxygen alkanediol.More preferably, this oxygen-alkanediol can be a straight chain.Being used for exemplary lipophilic phase component commodity of the present invention is called
Figure C200380107379004912
With
Figure C200380107379004913
See United States Patent (USP) 5,342,625.
In other embodiments, hydrophilic phase components can comprise one or more other compositions.Yet preferably other composition comprises that vitamin D compounds therein can abundant dissolved material, and this aqueous favoring composition can be used as the carrier of vitamin D compounds and can prevent that vitamin D compounds from coming to harm like this.Other possible hydrophilic phase components includes but not limited to low grade for alkanol, as C 1-C 5Alkanol, preferred alcohol.In preferred embodiments, this hydrophilic phase components contains 1, the 2-propylene glycol.
In certain embodiments, any pharmaceutical preparation of the present invention also can contain one or more additives as pre-concentration Emulsion.The additive that this field is known comprises but is not limited to: antitack agent, antifoaming agent, buffer agent, antioxidant such as ascorbic palmitate, Yoshinox BHT (BHT) and butylated hydroxyanisol (BHA) and tocopherol such as alpha-tocopherol (vitamin E), antiseptic, chelating agen, viscosity modifier, analeptic, aromatic, coloring agent, deodorizer, opacifier, suspending agent, binding agent, filler, plasticizer, lubricant and their mixture.Those skilled in the art are not difficult to determine to reach the amount of the additive that desired properties needs.
In other embodiments, additive also can comprise thickening agent and salt thereof.For various reasons, thickening agent can include but not limited to provide a kind of slow releasing function.When yet desire was oral, thickening agent did not generally need, and generally was not suitable for yet.Thickening agent generally is used for the part.Suitable thickening agent known in the art includes but not limited to pharmaceutically acceptable polymer and inorganic matter.In preferred embodiments, thickening agent includes but not limited to polyacrylic acid and polyacrylic acid copolymerized resin, polyacrylic acid and polyacrylic acid/methacrylic resin, cellulose and cellulose derivative.In certain embodiments, cellulose derivative includes but not limited to acylated cellulose, as cellulose acetate ester, Cellacefate ester, cellulose acetate succinate ester and Hydroxypropyl Methylcellulose Phathalate ester.Cellulosic salt and cellulose derivative include but not limited to sodium carboxymethyl cellulose.The cellulose derivative of preference includes but not limited to alkylcellulose, as methyl, ethyl, propyl cellulose; Hydroxy alkyl cellulose such as hydroxypropyl cellulose and hydroxypropylalkylce,lulose.Hydroxypropylalkylce,lulose includes but not limited to hydroxypropyl emthylcellulose.
In certain embodiments, other additive that can be used as thickening agent comprises but is not limited to polyvinylpyrrolidone, as-N-vinylpyrrolidone and nvp copolymer.Nvp copolymer includes but not limited to vinylpyrrolidone-ethylene acetate copolymer, polyvinyl resin such as polyvinyl acetate and polyvinyl alcohol and polymeric material.In other embodiments, the polymerism additive comprises but is not limited to Huang and has a liking for glue, arabic gum, alginate such as alginic acid and alginate such as sodium alginate.In certain embodiments, inorganic thickening agent is fit to, and includes but not limited to active hargil, bentonite and silicate.Silicate includes but not limited to hydrophilic silica product such as alkanisation silica gel, preferable methyl silica gel.In preferred embodiments, inorganic thickening agent is the silica colloidal product.
In certain embodiments, lipophilic phase component can suitably exist, and its amount accounts for about 30-90% of said composition gross weight.In preferred embodiments, the lipophilic phase component amount that can exist accounts for about 50-85% of said composition gross weight.
In other embodiments, one or more surfactants can suitably exist, and its amount accounts for about 1-50% of said composition gross weight.In preferred embodiments, the amount of one or more surfactants existence accounts for about 5-40% of said composition gross weight.More preferably the amount of one or more surfactants existence accounts for about 10-30% of said composition gross weight.
The amount of vitamin D compounds may be different because of various factors in the compositions.Make the different factor example of amount of vitamin D compounds include but not limited to the amount that route of administration and other chemical compound exist.In certain embodiments, the vitamin D compounds amount that can exist accounts for about 0.005-20% of said composition gross weight.In certain embodiments, the vitamin D compounds amount that can exist accounts for about 0.01-15% of said composition gross weight.In preferred embodiments, the vitamin D compounds amount that can exist accounts for about 0.1-10% of said composition gross weight.
In certain embodiments, the hydrophilic phase components amount that can exist accounts for about 2-20% of said composition gross weight.In other embodiments, the hydrophilic phase components amount that can exist accounts for about 5-15% of said composition gross weight.In preferred embodiments, the hydrophilic phase components amount that can exist accounts for about 8-12% of said composition gross weight.
In certain embodiments, pre-concentration Emulsion can be semi-solid.Semi-solid preparation can contain, and for example, one or more lipophilic phase component, the amount of its existence account for about 60-80% of said composition gross weight.The amount that one or more surfactants exist accounts for about 5-35% of said composition gross weight.The amount that one or more vitamin D compounds exist accounts for about 0.01-15% of said composition gross weight.
In certain embodiments, pre-concentration Emulsion can be liquid.Liquid preparation can contain, one or more lipophilic phase component for example, and the amount of its existence accounts for about 50-60% of said composition gross weight.The amount that one or more surfactants can exist accounts for about 4-25% of said composition gross weight.The amount that one or more vitamin D compounds exist accounts for about 5-10% that about 0.01-15% of said composition gross weight and amount that one or more hydrophilic phase components exist account for the said composition gross weight.
Adoptable other compositions comprises following compositions, and wherein the percentage ratio of each ingredients constitute said composition gross weight does not comprise active vitamin D compounds:
A Gelucire 44/14 about 50%
Miglyol 812 about 50%
B Gelucire 44/14 about 50%
Vitamin E TPGS gives 10% greatly
Miglyol 812 about 40%
C Gelucire 44/14 about 50%
Vitamin E TPGS about 20%
Miglyol 812 about 30%
D Gelucire 44/14 about 40%
Vitamin E TPGS about 30%
Miglyol 812 about 30%
E Gelucire 44/14 about 40%
Vitamin E TPGS about 20%
Miglyol 812 about 40%
F Gelucire 44/14 about 30%
Vitamin E TPGS about 30%
Miglyol 812 about 40%
G Gelucire 44/14 about 20%
Vitamin E TPGS about 30%
Miglyol 812 about 50%
H vitamin E TPGS about 50%
Miglyol 812 about 50%
I Gelucire 44/14 about 60%
Vitamin E TPGS about 25%
Miglyol 812 about 15%
J Gleucire 50/13 about 30%
Vitamin E TPGS about 5%
Miglyol812 about 65%
K Gelucire 50/13 about 50%
Miglyol 812 about 50%
L Gelucire 50/13 about 50%
Vitamin E TPGS about 10%
Miglyol 812 about 40%
M Gelucire 50/13 about 50%
Vitamin E TPGS about 20%
Miglyol 812 about 30%
N Gelucire 50/13 about 40%
Vitamin E TPGS about 30%
Miglyol 812 about 30%
O Gelucire 50/13 about 40%
Vitamin E TPGS about 20%
Miglyol 812 about 40%
P Gelucire 50/13 about 30%
Vitamin E TPGS about 30%
Miglyol 812 about 40%
Q Gelucire 50/13 about 20%
Vitamin E TPGS about 30%
Miglyol 812 about 50%
R Gelucire 50/13 about 60%
Vitamin E TPGS about 25%
Miglyol 812 about 15%
S Gelucire 44/14 about 50%
PEG 4000 about 50%
T Gelucire 50/13 about 50%
PEG 4000 about 50%
U vitamin E TPGS about 50%
PEG 4000 about 50%
V Gelucire 44/14 about 33.3%
Vitamin E TPGS about 33.3%
Miglyol 812 about 33.3%
W Gelucire 50/13 about 33.3%
Vitamin E TPGS about 33.3%
PEG 4000 about 33.3%
X Gelucire 44/14 about 50%
Vitamin E TPGS about 50%
Y Gelucire 50/13 about 50%
Vitamin E TPGS about 50%
Z Vitamin E TPGS about 5%
Miglyol 812 about 95%
Aa Vitamin E TPGS about 5%
Miglyol 812 about 65%
PEG 4000 about 30%
Ab Vitamin E TPGS about 10%
Miglyol 812 about 90%
Ac Vitamin E TPGS about 5%
Miglyol 812 about 85%
PEG 4000 about 10%; With
Ad Vitamin E TPGS about 10%
Miglyol 812 about 80%
PEG 4000 about 10%
Gastrointestinal tract external administration dosage form
In certain embodiments, but pharmaceutical preparation gastrointestinal tract external administration.Can give dosage form outside the gastrointestinal tract through various approach, include but not limited to intravenous, include but not limited to medicine group and fluid infusion, intramuscular and intra-arterial.In preferred embodiments, the outer dosage form of gastrointestinal tract be sterilization or can before giving the patient, sterilize because medicine will be walked around patient's natural anti-pollution barrier usually.The example of the outer dosage form of gastrointestinal tract includes but not limited to prepare the solution that is used for injecting, preparation is dissolved or suspended in pharmaceutically acceptable carrier when injecting dry products, suspension and the emulsion that preparation is used to inject.Being used for preparation of the present invention includes but not limited to This is a present commercially available vitamin D compounds intravenous formulations, contains 1 μ g calcitriol, 4mgPolysorbate 20 (polysorbas20), 2.5mg sodium ascorbate and optional with HCl or NaOH adjusting pH.
It is well known to those skilled in the art can be used to the suitable carrier of the outer dosage form of gastrointestinal tract of the present invention is provided.In certain embodiments, the suitable outer dosage form carrier of gastrointestinal tract includes but not limited to water for injection USP; The aqueous carrier includes but not limited to: sodium chloride injection, ringer's inj, glucose injection, dextrose ﹠ sodium chloride injection, newborn acidifying ringer's inj; Can include but not limited to water-soluble mixed carrier: ethanol, Polyethylene Glycol and polypropylene glycol; Include but not limited to non-aqueous carrier: Semen Maydis oil, Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, Oleum sesami, ethyl oleate, Semen Myristicae isopropyl ester and benzyl benzoate.
In other embodiments, can will there be the chemical compound that improves this pharmaceutical preparation dissolubility to join in the outer dosage form of gastrointestinal tract.For example, can utilize cyclodextrin and derivant thereof to improve the dissolubility of thalidomide (thalidomide) congener and derivant thereof.See for example United States Patent (USP) 5,134,127, it is for referencial use to fit into this paper in it.
The preparation of product item
The present invention also comprises the drug products of finishing the packing and posting label.This preparation item comprises suitable unit dosage forms, packs into sealed suitable utensil or container, in vial or other container.Just be fit to the dosage form of gastrointestinal tract external administration, preferred active one or more vitamin D compounds, more preferably calcitriol carries out degerming, is suitable as no particle solution administration.In other words, present invention includes outer solution of gastrointestinal tract and lyophilizing powder, degerming separately, and the latter is suitable for the reconstruction before injection.Perhaps, this unit dosage forms is a kind of solid that is fit to oral administration.
In certain embodiments, this unit dosage forms is fit to the vein conveying.Therefore, the present invention also comprises solution, the solution that the suitable vein of preferred degerming is carried.In preferred embodiments, this dosage form is the solution that is fit to intravenously administrable, contains at least one unit dose at least a or multivitamin D chemical compound, as
Figure C20038010737900551
In a preferred embodiment that equates, this unit dosage form is a kind of Orally taken emulsion of pre-concentration, contains the calcitriol of the 15 μ g that have an appointment and the excipient of following approximate weight percentage ratio: 65%MIGLYOL 30%GELUCIRE
Figure C20038010737900553
5% vitamin E TPGS and Yoshinox BHT (BHT) and butylated hydroxyanisol (BHA) each about 0.05%.
As any drug products, the packaging material of design and container must the stability of this product of protection in storage and transportation.For example, can design and to protect the product lucifuge and keep away the stability that pyritous packaging material and container are protected this product.In addition, product of the present invention comprises operation instructions and how appropriately to treat the out of Memory data of disease or disease Xiang doctor, technician or patient's explanation.In other words, this preparation item comprises the explanation that indicates or point out the execution dosage regimen, includes but not limited to precise dosage and method for monitoring.
Specifically, preparation item provided by the invention comprises: packaging material are as box, bottle, pipe, bottle, container, vein (i.v) transfusion bag, cover etc.: as described in contain the pharmaceutical preparation of a dosage in the packaging material at least, wherein, described pharmaceutical preparation comprises one or more vitamin D compounds, preferably active, more preferably calcitriol, comprise operation instructions in the described packaging material, point out that available described vitamin D compounds is treated MDS or alleviated its symptom by given dose described in the book and the specific dosage administration of employing.Say that more specifically preparation item provided by the invention comprises: packaging material such as box, bottle, pipe, bottle, container, vein (i.v) transfusion bag, cover etc.; In described packaging material, contain the pharmaceutical preparation of a unit dose at least, wherein, described pharmaceutical preparation comprises one or more vitamin D compounds, preferably active, more preferably calcitriol, comprise operation instructions in the described packaging material, point out, available described vitamin D compounds treatment MDS by given dose described in the book and the specific dosage administration of employing.
Preparation item provided by the invention comprises: packaging material such as box, bottle, pipe, bottle, container, vein (i.v) transfusion bag, cover etc.; In described packaging material, contain the pharmaceutical preparation of a unit dose at least, wherein, described pharmaceutical preparation comprises one or more vitamin D compounds, preferably active, more preferably calcitriol, other medicines preparation comprise the treatment preparation beyond the vitamin D compounds, comprise operation instructions in the wherein said packaging material, point out by given dose described in the book and the specific dosage administration of employing, available described Drug therapy MDS.Say that more specifically preparation item provided by the invention comprises: packaging material such as box, bottle, pipe, bottle, container, vein (i.v) transfusion bag, cover etc.; In described packaging material, contain each pharmaceutical preparation of a unit dose at least, wherein, a kind of pharmaceutical preparation comprises one or more vitamin D compounds, another kind of pharmaceutical preparation comprises other treatment preparation beyond the vitamin D compounds, comprise operation instructions in the described packaging material, point out by given dose described in the book and the specific dosage administration of employing, available described preparation for treating MDS.
Preparation item provided by the invention comprises: packaging material such as box, bottle, pipe, bottle, container, vein (i.v) transfusion bag, cover etc.; At least contain each pharmaceutical preparation of a unit dose in described packaging material, wherein, a kind of pharmaceutical preparation comprises one or more vitamin D compounds, and is preferably active, more preferably calcitriol; Another kind of pharmaceutical preparation comprises one or more hemopoietic growth factors or cytokine, preferred r-HuEPO, r-metHuG-CSF or their combination; Wherein, described packaging material comprise operation instructions, point out by given dose described in the book and the specific dosage administration of employing, available described Drug therapy MDS.Say that more specifically preparation item provided by the invention comprises: packaging material such as box, bottle, pipe, bottle, container, vein (i.v) transfusion bag, cover etc.; At least contain each pharmaceutical preparation of a unit dose in described packaging material, wherein, a kind of pharmaceutical preparation comprises one or more vitamin D compounds, and is preferably active, more preferably calcitriol; Another kind of pharmaceutical preparation comprises one or more hemopoietic growth factors or cytokine, preferred r-HuEPO, r-metHuG-CSF or their combination; , comprise operation instructions in the described packaging material, point out by given dose described in the book and the specific dosage administration of employing, available described preparation for treating MDS.
In preferred embodiments, appended operation instructions in this preparation item indicate or point out before or after administration time or a plurality of time will monitor the plasma concentration of calcium.For example, appended operation instructions are pointed out in the preparation item, can and give the one or many subsequent dose before giving for the first time dosage after, measure blood calcium concentration.In one embodiment, appended operation instructions point out that available vitamin D compounds is treated the MDS patient of blood calcium concentration less than about 10.5mg/dL in the preparation item.In another embodiment, appended operation instructions point out that available vitamin D compounds is treated the anemia of blood calcium concentration less than the MDS patient of about 10.5mg/dL in the preparation item.
The appended information material that is used for the treatment of MDS or alleviates its one or more symptoms points out that also hypercalcemia patient can not contain the pharmaceutical composition of vitamin D compounds in this preparation item.In one embodiment, the appended information material that is used for the treatment of MDS or alleviates its one or more symptoms is also pointed out in this preparation item, and 2 grades, 3 grades or 4 grades of hypercalcemia patients can not be with the medicine composite for curing that contains vitamin D compounds.
Embodiment
Pharmacokinetics after the embodiment 1 calcitriol administration
Be designed in the pharmacokinetics behavioral study of measuring preferred calcitriol peroral dosage form at one, taken not commensurability calcitriol for 12 objects.This preferred peroral dosage form (" preferred formulation ") contains 15 microgram calcitriols and following excipient and about percentage by weight thereof: 65%Miglyol
Figure C20038010737900571
30%Gelucire 5% vitamin E TPGS and Yoshinox BHT (BHT) and butylated hydroxyanisol (BHA) each about 0.05%.Wherein 3 objects are taken 15 μ g, 3 and are taken 30 μ g, take 60 these preferred formulations of μ g (calcitriol) for 6.(" after the administration ") 0.5,1,1.5,2,3,4,6,8,12,24,48 and 72 hour taking blood sample after before giving first dose of this preferred formulation administration, reaching.Analyze the calcitriol level with the commercialization radioimmunoassay.Mean plasma concentration of each group of making is seen Fig. 1 to the curve of time.
Calculate the non-separation pharmacokinetic parameter of each object, table 1 is made in mean deviation then.Value after administration deducts the ossified triol of calcitriol baseline value correction endogenous.The maximum concentration (" C of the pharmacokinetic parameter blood plasma of calculating MAX"), reach time (" Tmax "), half-life the limit (" T of maximum concentration 1/2"), and measure concentration to 0-24 hour (" AUC 0-24"), 0-72 hour (" AUC 0-72") and the infinite (" AUC of heap of stone of time 0- 0-∞") the irregular quadrilateral area.
Pharmacokinetic parameter behind preferred calcitriol amount of formulation 15,30 of table 1 administration of human object and the 60 μ g
This pharmacokinetic data shows that this preferred formulation is reaction linear and that can estimate to improving problem, does not absorb saturated evidence.In addition, this pharmacokinetic data shows that the calcitriol amount that can induce hypercalcemia of originally thinking that gives has reached the plasma concentration high peaks.Therefore, the invention provides a kind of vitamin D compounds plasma concentration value of peaking that can make and treat MDS or alleviate its symptom, but do not cause the safe and effective method of hypercalcemia.
Embodiment 2 vitamin D single therapies
Following treatment procedure provides an example that adopts said method treatment MDS or alleviate its symptom.
The patient contains have an appointment 15 microgram calcitriols and following excipient and about percentage by weight thereof from clothes: 65%Miglyol
Figure C20038010737900581
30%Gelucire 5% vitamin E TPGS and Yoshinox BHT (BHT) and each preferred formulation of about 0.05% of butylated hydroxyanisol (BHA).Total dosage is 45 μ g calcitriols, or 3 15 μ g capsules, and is weekly, each full clothes.Monitor the patient week about once, the administration number of times of calcitriol and dosage can be adjusted according to treatment time length.
The monitoring patient comprises that health check-up, ECOG behavior state, blood test, anemia observation, blood testing, urinalysis, research drug administration, blood transfusion record, side effect, companion make biopsy, peripheral blood film inspection, endogenous EPO and ferrum state with medicine, FACT-An application form, suction bone marrow.
Embodiment 3 vitamin D therapeutic alliance programs
Following treatment procedure provides another example that adopts said method treatment MDS or alleviate its symptom.
The patient contains have an appointment 15 microgram calcitriols and following excipient and about percentage by weight thereof from clothes: 65%Miglyol 30%Gelucire
Figure C20038010737900584
5% vitamin E TPGS and Yoshinox BHT (BHT) and each preferred formulation of about 0.05% of butylated hydroxyanisol (BHA).Total dosage is 45 μ g calcitriols, or 3 15 μ g capsules, and is weekly, each full clothes.Monitor the patient week about once, the administration number of times of calcitriol and dosage can be adjusted according to treatment time length.
The monitoring patient comprises that health check-up, ECOG behavior state, blood test, anemia observation, blood testing, urinalysis, research drug administration, blood transfusion record, side effect, companion make biopsy, peripheral blood film inspection, endogenous EPO and ferrum state with medicine, FACT-An application form, suction bone marrow.
Also monitor the patient with conclusive they whether be to be responder or nonresponder to the red of vitamin D compounds administration.The red of majority is that responder is that original haemachrome baseline level is lower than 11g/dL, but is increased to more than or equal to 2g/dL from this baseline through treatment.The red of minority is that responder is that original haemachrome baseline level is lower than 11g/dL, but is increased to 1-2g/dL through treatment from this baseline.Responder continues to take the calcitriol same number of same dose, but not responder begins to obey EPO and vitamin D compounds.The initial dose of EPO is 10000U once a day.If the back nothing improvement of 6 weeks, the amount of EPO is increased to 20000U once a day.The subcutaneous EPO that gives, and monitoring patient's ferrum state.
Embodiment 4 clinical trials
Low danger MDS and refractory anemia enter the clinical trial of 2 time limits to estimate the effect that the high dose pulse gives calcitriol to the unresponsive patient of erythropoietin.These patients depend on red cell transfusions because serious anemia is arranged.Patient is the calcitriol of orally give 45 μ g dosage weekly, continues for 20 weeks.Calcitriol is formulated in and contains following excipient and about percentage by weight is: 65%Miglyol
Figure C20038010737900591
30%Gelucire
Figure C20038010737900592
In the compositions of 5% vitamin E TPGS and Yoshinox BHT (BHT) and each preferred formulation of about 0.05% of butylated hydroxyanisol (BHA).By measuring the active reaction of haemachrome and hematocrit levels monitoring patient to calcitriol, but and the blood transfusion number of times that will give during will treat make comparisons with the ratios of preceding the 8 weeks observation time limits acquisitions of treatment.
Patient #1 performance haemachrome has been formed " less important reaction " scheme (Fig. 2 A) that is defined as than more than the baseline values rising 1g/dL
Patient #2 display requirement red cell transfusions reduces by 50% (Fig. 2 B) than baseline.Patient #3 demonstration haemachrome has been formed " dominant response " scheme (Fig. 2 C) that is defined as than more than the baseline rising 2g/dL.All these patients' result shows that it is effective that the high dose pulse gives calcitriol treatment MDS.
Various embodiments of the present invention have now been described.These are described and the embodiment purpose is elaboration the present invention and unrestricted.Those skilled in the art will know that maybe and can determine have many normal experiment methods suitable with specific embodiments of the present invention described herein.These suitable methods are included in following claims.
All to include this paper in for referencial use in mentioned all publications, patent and patent application in this description, and it specifically and is individually pointed out to include in for referencial use identical of this paper with reference to degree and each publication, patent or application for patent.

Claims (36)

1. the application of one or more vitamin D compounds of high dose in the medicine of preparation treatment osteomyelodysplasia syndrome.
2. application as claimed in claim 1 wherein gives one or more vitamin D compounds and was no more than once in per 3 days.
3. application as claimed in claim 1 wherein gives one or more vitamin D compounds and is about weekly and is no more than once.
4. application as claimed in claim 1, wherein the high dose of one or more vitamin D compounds is to be about 3-300 μ g.
5. application as claimed in claim 1, wherein the high dose of one or more vitamin D compounds is to be about 5-200 μ g.
6. application as claimed in claim 1, wherein the high dose of one or more vitamin D compounds is to be about 15-105 μ g.
7. application as claimed in claim 1, wherein the high dose of one or more vitamin D compounds is to be about 15-90 μ g.
8. application as claimed in claim 1, wherein the high dose of one or more vitamin D compounds is to be about 20-80 μ g.
9. application as claimed in claim 1, wherein the high dose of one or more vitamin D compounds is to be about 35-75 μ g.
10. application as claimed in claim 1, wherein the high dose of one or more vitamin D compounds is to be about 30-60 μ g.
11. application as claimed in claim 1, wherein the high dose of one or more vitamin D compounds is about 45 μ g.
12. application as claimed in claim 1, wherein the dosage that gives of one or more vitamin D compounds can reach the plasma peaks of vitamin D compounds at least about 0.5nM.
13. application as claimed in claim 1, wherein at least a vitamin D compounds is a calcitriol.
14. application as claimed in claim 1, wherein one or more vitamin D compounds pass through intravenously administrable.
15. the application of one or more vitamin D compounds of high dose in the medicine of the relevant anemia of preparation treatment MDS.
16. application as claimed in claim 15 wherein gives one or more vitamin D compounds and was no more than once in per 3 days.
17. application as claimed in claim 15 wherein gives one or more vitamin D compounds and is no more than once weekly.
18. application as claimed in claim 15, the high dose that wherein gives one or more vitamin D compounds is about 3-300 μ g.
19. application as claimed in claim 15, wherein the high dose of one or more vitamin D compounds is about 5-200 μ g.
20. application as claimed in claim 15, wherein the high dose of one or more vitamin D compounds is about 15-105 μ g.
21. application as claimed in claim 15, wherein the high dose of one or more vitamin D compounds is about 15-90 μ g.
22. application as claimed in claim 15, wherein the high dose of one or more vitamin D compounds is about 20-80 μ g.
23. application as claimed in claim 15, wherein the high dose of one or more vitamin D compounds is about 35-75 μ g.
24. application as claimed in claim 15, wherein the high dose of one or more vitamin D compounds is about 30-60 μ g.
25. application as claimed in claim 15, wherein the high dose of one or more vitamin D compounds is about 45 μ g.
26. application as claimed in claim 15, wherein the dosage that gives of one or more vitamin D compounds can reach the plasma peaks of vitamin D compounds at least about 0.5nM.
27. application as claimed in claim 15, wherein at least a vitamin D compounds is a calcitriol.
28. application as claimed in claim 15, wherein one or more vitamin D compounds pass through intravenously administrable.
29. as claim 1 or 15 described application, wherein said medicine also contains lipophilic phase component and surfactant.
30. application as claimed in claim 29, wherein said lipophilic agent is MIGLYOL 812.
31. application as claimed in claim 29, wherein said surfactant are vitamin E TPGS.
32. application as claimed in claim 29, wherein said medicine also comprise about 50%MIGLYOL 812 and about 50% vitamin D TPGS.
33. application as claimed in claim 29, wherein said medicine also comprise at least a additive that is selected from antioxidant, buffer agent, antifoaming agent, antitack agent, antiseptic, chelating agen, viscosity modifier, analeptic, aromatic, coloring agent, deodorizer, opacifier, suspending agent, binding agent, filler, plasticizer, thickening agent, lubricant and composition thereof.
34. application as claimed in claim 33, a kind of in the described additive is antioxidant.
35. application as claimed in claim 34, wherein said antioxidant is selected from Yoshinox BHT and butylated hydroxyanisol.
36. application as claimed in claim 35, wherein said unit dosage forms comprises Yoshinox BHT and butylated hydroxyanisol.
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* Cited by examiner, † Cited by third party
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